CN1578650A - Compositions for the treatment of infectious diseases - Google Patents

Abstract

Described herein are compositions and methods for the treatment of microbial infection.

Description

Compositions for treating infectious diseases

Background

Reactive oxygen metabolites are often produced by incomplete reduction of oxygen. One molecule of O₂Complete reduction to water is a 4-electron process. Oxidative metabolism continues to produce partially reduced oxygen in proportion to O₂It is more active and therefore more toxic. Reduction of O by one electron₂Generating super oxide ion (O)₂ ^-) (ii) a Reduced by another electron to produce hydrogen peroxide (H)₂O₂) And is reduced by a third electron to generate hydroxyl (OH) and a further electron to generate hydroxide ion. Nitrous Oxide (NO) is another reactive oxygen metabolite of interest, produced by other pathways. In particular, hydroxyl radicalHave a very high activity and appear to be the most potent mutagen derived from ionizing radiation. If the organism is to survive, all of these types will be produced and must be converted to less active types.

As an effector mechanism, specific cells of the immune system control the toxic effects of the ROMs. Professional phagocytes, polymorphonuclear leukocytes (neutrophils, PMNs), monocytes, macrophages, and eosinophils serve to protect the host from infection by searching out and destroying invading microorganisms. These phagocytic cells possess a membrane-bound enzyme system that can be activated to produce toxic oxygen radicals in response to a wide variety of stimuli.

It is reported and believed that "increased phagocytosis breathing" (bursty breathing) is the result of increased mitochondrial activity that provides additional energy for the phagocytosis process. It was subsequently demonstrated that non-mitochondrial enzyme systems produce increased levels of oxygen metabolism even in the presence of mitochondrial inhibitors such as cyanide and antimycin a before sudden breathing persists. Paul and Sbarra clearly demonstrated the stimulation of phagocytic cells to produce hydrogen peroxide in 1968, and Babior and colleagues demonstrated superoxide as the major product of oxidase in 1973. See Paul and Sbara, Biochim Biophys Acta156 (1): 168-78 (1968); babior, et al, J Clin Invest52 (3): 741-4(1973). It is now generally accepted that the enzyme is membrane bound and exhibits a response to NADPH (K)_m45 μ M) alignment of NADH (K)_m450 μ M) and converts oxygen to its one electron reduction product, superoxide.

The hydrogen peroxide causes subsequent superoxide disproportionation.

The enzyme activity is hardly measurable in resting (unstimulated) phagocytes, but is dramatically increased by stimulation. Patients with the rare genetic disease Chronic Granulomatosis (CGD) have a propensity for severe chronic recurrent infection. Neutrophils from these patients phagocytose foreign material normally, but lack burst respiration and NADPH oxidase activity (and free radical (radial) products) cannot be measured, indicating that oxidase and its products, reactive oxygen metabolites, have important bactericidal functions.

Neutrophils and macrophages produce oxidants to break through the protective layer or other factors that protect bacteria from phagocytosis. Large amounts of superoxide, hydrogen peroxide and hydroxyl ions are lethal to most bacteria even when found in very small amounts.

While these oxygen metabolites have beneficial effects, it is clear that inappropriate production of oxygen metabolites may lead to serious detrimental effects. Many deleterious effects are manifested in the skin tissue and mucosa of the host. For example, harmful concentrations of reactive oxygen metabolites can exacerbate a variety of infections including helicobacter pylori, tinea, and trypanosome infections. Effective compositions and methods to reduce or minimize the production and release of ROMs in patients suffering from a variety of different diseases would be highly beneficial to medicine and would be suitable for reducing or eliminating a significant amount of human suffering.

Topical administration of ointments, analgesics, and other such agents is well known in the art. The use of mud or plant extracts such as aloe vera are just two examples of such agents. For a discussion of aloe vera, see U.S. patent No.4,857,328. The use of two different histamine derivatives as topically administered dermal agents has also been previously discussed. The first can be seen in the series of U.S. patents to Jack et al, which disclose the use of a pharmaceutical composition of water, a water-soluble vinyl polymer gel amine alcohol dispersion and 1H-imidazole-4-ethane phosphate to treat certain skin disorders. See U.S. patent nos. 5,294,440, 5,679,337, and 5,716,610. A second, disclosed in U.S. Pat. No.5,792,784, is a pseudodipeptide product obtained by coupling histamine or methyl-substituted histamine with an amino acid.

Description of The Preferred Embodiment

The following description relates to compositions and methods for treating microbial infections such as bacterial, protozoal, yeast, fungal, parasitic and other parasitic infections. The compositions and methods are useful for treating certain conditions caused by a variety of disease etiologies. Examples of infections include helicobacter pylori infections, which are believed to cause ulcers and other gastrointestinal disorders, and infections caused by streptococci, which are believed to cause impetigo, erysipelas, cellulitis, necrotizing fasciitis, wound infections, toxic shock-like syndrome caused by streptococci, postpartum fever, rheumatic fever, glomerulonephritis, erythema nodosum, and scarlet fever.

While the precise mechanisms by which the compositions and methods described herein act are not well understood, the application guesses why the agents disclosed herein are effective in treating such a wide range of infectious conditions. One theory supports that once an invading organism, such as bacteria, protozoa, yeasts, fungi, parasites and other parasites invade a host, the host initiates an inflammatory response to the invader. Inflammation is typically characterized by local vasodilation, increased local blood flow, increased capillary permeability with large amounts of fluid leaking into the interstitial spaces, and other local and systemic effects. Shortly after inflammation occurs, neutrophils, macrophages and other cells invade the inflammatory region. These cells begin to clear the tissue of infectious or toxic components. One method by which these cells are used to protect the body from harmful foreign substances involves the production and release of reactive oxygen metabolites.

A variety of Reactive Oxygen Metabolites (ROMs) are produced in the monovalent pathway of oxygen reduction. These ROMs are enzymatically produced by phagocytic cells such as monocytes and polymorphonuclear neutrophils (PMNs) and are released continuously in the burst breath. Hydrogen peroxide and other ROMs play an important role in the immune defense of the host. However, excessive or inappropriate times or locations of production of the ROMs may appear to damage the cells and tissues of the host, and may therefore be harmful to the host.

The effects produced by ROMs are multiple. It is known that ROMs cause apoptosis in NK cells. It is also known that ROMs cause anergy and apoptosis in T-cells. However, some believe that the ROMs cause cell death by disrupting the cell membrane and by altering the pH of cellular pathways important for cell survival.

Furthermore, phagocytes that undergo sudden breathing and produce and release large amounts of ROMs also produce and release secondary cytokines such as tumor necrosis factor- α (TNF- α) and interleukin-1 (IL-1). an example of secondary cytokine-mediated cell damage is found in the Schwartzmann reaction, where neutrophil-mediated cell damage is believed to be activated by TNF and IL-1 (Imamura S, et al, "invasion of tumor progression factor-alpha, inter leukin-1 beta, inter leukin-8, and inter leukin-1 receptor agonist in acid nuclear fusion captured by local defense" Pathol int.47 (1): 16-24 (1997)).

The work described herein is a surprising discovery that compounds that reduce or inhibit the number of ROMs produced or released by multiple sources in a subject can help treat and recover individuals suffering from multiple microbial infections. While there may be involvement of the sole or distinct (may be separated) underlying etiological causes of these microbial infections, the compositions and methods described herein have a broad role in their overall treatment. A possible explanation for the general efficacy of the compositions and methods described herein is that each of the different organisms discussed above share a common feature in that oxidative damage caused by inappropriate and harmful concentrations of ROMs mediated by enzymatically produced ROM exacerbates their resulting condition. Regardless of the precise mechanism of action of the compounds and methods described herein, administration of compounds that inhibit the production or release of or scavenge ROMs, alone or in combination with other beneficial compounds, provides an effective treatment for a variety of microbial infections.

The methods and compounds described herein are useful for treating a variety of microbial infections. For example, the methods and compounds described herein are useful for treating parasitic, fungal, yeast, protozoan and bacterial infections, including treatment of, for example, staphylococcal (staphylococcus), streptococcal (steptococcual), enterohemangiologic, clostridium, neisseria, spirillum, chlamydia, tinea, candida, mycobacteria, and trypanosoma infections, either alone or in combination with other therapeutic compounds. The compounds and methods described herein are also useful for treating skin disorders such as acne, cervical acne keloids (acne keloidalis nuchae), acne necrosis (acne necrotica), acne urtica, actinic keratosis (actinic keratoses), acute febrile neutrophilic dermatosis, allergic contact dermatitis, alopecia areata, androgenetic alopecia (androgenetic alopecia), atopic dermatitis, blue nevus (blue naevus), basal cell carcinoma, furuncle, bullous emphiigo, candida, chilblain, chloasma, acne chloride, nodular cartilage dermatitis, pigmented mycosis, dermatitis, dermatofibroma, eczema, erythrasma, folliculitis, fungal infections of the hand and foot, mouth disease (hand foot and mouth disease), head lice, scytitis, melanoma, vegetal dermatitis, alpha infections, lipoid necrosis, papuloid necrosis, urticaria, paronychia, psoriasis, acne, scabies, acne vulgaris (scabies), acne vulgaris (pilomatous folliculitis), scabies, and scabies, Scleroderma, seborrheic dermatitis, shingles, tinea, urticaria, and other skin and mucosal conditions or disease states.

The compounds and methods described herein are also useful for treating gastrointestinal, muscle, eye, genitourinary, respiratory, blood, liver, kidney, pancreas, abdomen, throat, stomach, nasopharynx, and dental diseases. These compounds and methods are also used in combination with various traditional chemotherapeutic agents, generally to promote wound healing and to drive the healing process, and more recently to treat infections caused by parasites, protozoa, fungi, yeasts, bacteria and other human pathogens.

Preparation

Administration of a compound that inhibits or eliminates ROM production or release can be via intravenous, intraarterial, rectal, oral, reproductive, intramuscular, topical, transdermal, intranodal, or respiratory routes. To facilitate these routes of administration, various formulations of the compounds may be used. The formulations facilitate administration of compounds that inhibit the production or release of reactive oxygen metabolites or scavenge these compounds once released. In one embodiment, the formulations contemplated herein comprise a topical carrier suitable for administering an effective amount of a ROM-inhibiting and/or scavenging compound. In another embodiment, the formulations contemplated herein comprise a systemic carrier suitable for administration of an effective amount of a ROM inhibiting and/or scavenging compound.

In preferred embodiments, various histamine or histamine-derived compounds may be used to obtain a beneficial reduction in the concentration of enzymatically generated ROM production and release. The term "histamine" as used generally herein is embodied in a variety of histamine and histamine-related compounds. For example histamine, the dihydrochloride salt form of histamine (histamine dihydrochloride), histamine diphosphate, other histamine salts, esters or prodrugs and H₂Receptor agonists may be included in the definition of histamine.

Administration of compounds that induce the release of endogenous histamine from a patient's own tissue stores may also be useful in the treatment of microbial infections. For example, such compounds include IL-3 retinoic acid, other retinoids such as 9-cis-retinoic acid and all-trans-retinoic acid, and allergens. Other ROM production and release inhibiting compounds such as NADPH oxidase inhibitors like diphenyleneiodonium (diphenyleneiodonium) are also useful in conjunction with the methods described herein. Furthermore, local or systemic administration of 5-hydroxytryptamine and 5HT receptor agonists is also useful for the treatment of microbial infections.

Formulations containing the ROM inhibitors or scavenging compounds described herein are shown at concentrations effective for treating microbial diseases or infections. When the ROM inhibitor compound is included in the formulation, it is preferably included in a total concentration of from about 0.0001% to about 0.5% by weight of the formulation of such ingredient, more preferably from about 0.001% to about 0.01% by weight of the formulation, and most preferably from about 0.002% to about 0.05% by weight of the formulation.

The compositions and methods described herein are further intended to administer a variety of ROM scavengers in combination with the ROM production and release inhibiting compounds described above. Known ROMs scavengers include catalase, superoxide dismutase (SOD), glutathione peroxidase, and ascorbate peroxidase. Additionally, vitamins A, E and C are also known to have scavenging activity. Minerals such as selenium and manganese are also effective against ROM-mediated damage. The methods disclosed herein are intended to include the administration of the above compounds and those compounds having similar ROM inhibitory activity.

The compounds that scavenge ROMs may be administered in a total concentration of about 0.0001% to about 0.5% by weight of the formulation, more preferably about 0.001% to about 0.01% by weight of the formulation, and most preferably about 0.002% to about 0.05% by weight of the formulation. The formulation containing ROM scavenger is administered 1-10 times per day. In each case, the dosage and frequency of application depends on the activity of the compound administered and the cause of the infectious disease. The foregoing dosages are appropriate for the compounds listed above. Suitable dosages for any particular host can be readily determined by empirical techniques well known to those of ordinary skill in the art.

Non-enzymatic ROM scavengers can be administered in amounts determined empirically, well known to those of ordinary skill in the art. For example, vitamins A and E may be administered in doses of about 1-5000IU each time, 10-500 IU, and 100 IU and 300 IU. Vitamin C can be administered in doses of 1. mu.g to 10gm each. Minerals such as selenium and manganese may be administered in amounts of about 1 picogram to 1 milligram per dose. These compounds may also be administered as a protective or prophylactic treatment for ROM mediated disease states.

The preferred concentration ranges described above are generally effective to inhibit the production of or clear existing ROMs from the treatment area of the subject. Higher concentrations can also be used successfully. In addition, routine clinical evaluation can be used to optimize the compound dosing concentrations described herein. For example, histamine concentrations may modulate treatment of (accmod) infections on the basis of the cause and stage of the infection being treated. The concentration may also vary based on the carrier used as the formulation. Lotions designed to merge into the skin without visible traces may contain a low concentration of histamine when compared to an emulsion that dries out on the skin of the subject being treated. However, the liquid composition of histamine can be adapted for intravenous administration, alone or in combination with a chemotherapeutic agent, to facilitate the removal of pathogenic microorganisms from the body.

The concentration of the inhibitory or scavenging ROM compound can vary depending on the other ingredients used in the formulation. For example, when skin irritation reducing compounds such as strontium, aloe vera, chamomile, alpha-bisabolol, kola nut extract, green tea extract, tea tree oil, licorice extract, allantoin, urea, caffeine or other xanthines and glycyrrhizic acid and derivatives thereof are included, the histamine concentration may be reduced. Likewise, histamine concentrations may be reduced in liquids by mixing with saline solutions and additives known to those skilled in the art of intravenous liquid administration. These compounds may also be used in formulations in combination with the above compounds for inhibiting or scavenging ROM. These compounds may be added to the composition either individually or in combination with each other. The use of strontium as an anti-irritant for skin is described in U.S. patent No.5,804,203.

In addition, various antibiotics, antifungal agents, antiparasitic agents, and antiprotozoal agents contained in the compositions described herein may be included in the compositions described herein, examples of such agents include aminoglycosides, penicillins, antifungal agents such as amphotericin B, fluoroquinolones, tetracyclines, β -lactams, sulfonamides, and the like.

Compounds that cause stimulation of the immune system of the host, such as cytokines (e.g., IL-1, IL-2, IL-12, IL-15, IFN- α, IFN- β, IFN- γ, etc.), may also be included in the compositions described herein.

Suitable carriers and components for use with the formulations described herein are well known in the art. Such carriers include water; organic solvents such as alcohols (e.g., ethanol); glycols (such as propylene glycol); aliphatic alcohols (lanolin); mixtures of water and organic solvents and mixtures of organic solvents such as alcohols and glycerol; lipid-based substances such as fatty acids, acylglycerols (including oils, such as mineral oils, and fats from natural or synthetic sources), phosphoglycerides, sphingolipids, and waxes; protein-based substances such as collagen and gelatin; silicone based materials (non-volatile and volatile); hydrocarbon-based substances such as microsponges (microsponges) and polymer matrices; stabilizers and suspending agents; an emulsifier; and other carrier ingredients suitable for dermal administration, and mixtures of these ingredients with other ingredients known in the art. The carrier may additionally include ingredients suitable for improving the stability and efficacy of the formulation used, such as preservatives, antioxidants, dermal penetration enhancers and sustained release materials. Examples of these ingredients are described in the following references: Martindale-The Extra Pharmaceutical sciena (Pharmaceutical Press, London 1993) and Martin (ed.), Remington's Pharmaceutical Sciences.

The appropriate carrier is selected according to the particular substance form and mode of presentation to be achieved by the formulation. Examples of suitable forms include liquids (e.g., eye drops, aerosols, insufflation, inhalants, intravenous drip bags, in-device syringes (on-site injection systems), gargles, intramuscular injections, intraperitoneal (intraperitoneal) injections, subcutaneous injections of spinal fluid into the central nervous system, and mouthwashes); solids and semi-solids such as gels, foams, pastes (such as capsules, oral medications (including subliganal or buccal), pills, implantable devices, biodegradable timed release devices, chews, lozenges, special purpose pastes, and toothpaste compositions), creams, ointments, "sticks" (such as lipstick or underarm deodorant sticks), powders, and the like; formulations containing microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, such as hydroxymethylcellulose or gelatin microcapsules, respectively, or in colloidal drug delivery systems, such as liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules, or in microemulsions; rectal or vaginal suppositories, creams, foams, gels or other ointments; and other forms. An example of a toothpaste is found in U.S. patent No.4,307,076 which discusses toothpaste compositions.

The formulations described herein can be prepared in a variety of physical forms. For example, solids, pastes, creams, lotions, gels and aqueous liquids are all suitable formulation forms. The distinction between these forms is their physical appearance and viscosity, which can be adjusted by the appearance and amount of emulsifiers and viscosity modifiers present in the formulation. A particular topical formulation can often be prepared in a variety of these forms. Solids are generally hard and non-flowable, and are typically prepared as bars or sticks, or in a particular form; the solids may be opaque or transparent and may optionally contain solvents, emulsifiers, humectants, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product. Creams and lotions are often similar to each other, differing primarily in their viscosity; creams and lotions can be opaque, transparent or clear and often contain emulsifiers, solvents and viscosity modifiers, as well as humectants, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product. Gels can be prepared in a range of viscosities, from thick or high to thin or low. These formulations, like lotions and creams, may also contain solvents, emulsifiers, humectants, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product. Liquids are less viscous than creams, lotions or gels and are generally free of emulsifiers. Liquid products often contain solvents, emulsifiers, humectants, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product.

Suitable emulsifiers for use in the formulations described herein include, but are not limited to, ionic emulsifiers; benzetonium dimethyl sulfate, cetearyl alcohol; nonionic emulsifiers such as polyoxyethylene oleyl ether (polyoxyethyleneoleyl ether), PEG-40 stearate (sterate), ceteareth-12, ceteareth-20, ceteareth-30, ceteareth-halchol, PEG-100 stearate, glyceryl stearate or combinations or mixtures thereof.

Suitable viscosity modifiers for use in the formulations described herein include, but are not limited to, protective colloids or nonionic resins such as hydroxyethylcellulose, xanthan gum, magnesium aluminum silicate, silica, microcrystalline wax, beeswax, paraffin and spermaceti, combinations or mixtures thereof.

Suitable solvents for use in the formulations described herein include, but are not limited to, water, ethanol, butylene glycol, propylene glycol, isopropanol, isoprene glycol (isoprene glycol), and glycerol. Additionally, combinations or mixtures of these solvents may be used in the formulations described herein.

Suitable surfactants for use in the formulations described herein include, but are not limited to, nonionic, amphoteric, ionic, and anionic surfactants. For example, dimethicone copolyol, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, lauramide DEA, cocamide DEA, and cocamide MEA, oleyl betaine, cocamidopropyl phosphatidyl PG-dimonium chloride, and amomoniumlauseth sulfate are contemplated for use with the formulations disclosed herein. In addition, combinations or mixtures of these surfactants can be used in particular embodiments of the disclosed formulations.

Suitable preservatives for use in particular embodiments of the disclosed formulations are, but are not limited to, antimicrobials such as methyl paraben, propyl paraben, sorbic acid, benzoic acid, and formaldehyde, as well as natural (physical) stabilizers, and antioxidants such as vitamin E, sodium ascorbate/ascorbic acid, and propyl gallate. In addition, combinations or mixtures of these preservatives may be used in particular embodiments of the disclosed formulations.

Suitable humectants for use in particular embodiments of the disclosed formulations include, but are not limited to, lactic acid and other hydroxy acids and their salts, glycerin, proplyene glycol, and butylene glycol. Suitable emollients include lanolin alcohols, lanolin derivatives, cholesterol, petrolatum, iso stearate pivalate and mineral oil. In addition, combinations or mixtures of these humectants and emollients may be used in particular embodiments of the disclosed formulations.

In addition to the ROM production and release inhibiting compounds used in specific embodiments of the disclosed formulations, suitable active ingredients include, but are not limited to, fruit acids, sunscreens, anti-acne medications, vitamins and minerals, and various prescription and over-the-counter medications. An example of a sunscreen can be found in U.S. patent No.5,160,731. Embodiments of the disclosed summons can also include various added active ingredients such as those described above.

Suitable fragrances and pigments for use in particular embodiments of the disclosed formulations include, but are not limited to, FD & C Red No.40 and FD & C Yellow No. 5. Other examples of fragrances and pigments suitable for use in topical products are known in the art.

Other suitable additional ingredients that may be included in particular embodiments of the disclosed formulations include, but are not limited to, abrasives, absorbents, anti-caking agents, anti-foaming agents, anti-static agents, astringents (e.g., witch hazel tincture, alcohol, and herbal extracts such as chamomile extract), binders/excipients, buffering agents, chelating agents, film forming agents, conditioning agents, opacifiers, pH adjusters, and pesticides. Examples of each of these ingredients in topical product formulations can be found in The publications of The Cosmetic, Toiletry, and Fragrance Association (CTFA). See, e.g., CTFA Cosmetic Ingredient Handbook, 2^nd edition，eds.John A.Wenninger and G.N.McEwen，Jr.(CTFA，1992)。

A variety of product types, including specific cosmetics, can also be prepared in each of the above-described forms (e.g., solids, creams, lotions, gels, and liquids). For example, cleansers (such as soap), shampoos/conditioners, cosmetics, and other facial, hand, and body products may be prepared in any of the product forms described above: solids, creams, lotions, gels and liquids. Typical solid product forms include: suppositories, cosmetics such as lipsticks, pills, capsules, blushers (blushes), other cosmetics, lozenges, implants, controlled release devices, oral pills, deodorant and suppositories. Typical cream and lotion form products include: urogenital lather (urogenic lather), skin care products, sunscreens, shampoos/conditioners and other hair care products, and other cosmetics such as foundation creams. Typical gel products include: oral capsules, anti-acne lotions (solubilions) and skin conditioners. Typical liquid form products include: intravenous drip bags, intra-arterial drip bags, intramuscular injections, inhalants, aerosols, spinal fluid injections, insufflators, eye drops, nasal sprays, on-site injectable systems, aerosol inhalants (vapors), soaking agents, detergents, swallows, nail polish (for the treatment of tinea and other fungal nail growth), anti-acne lotions, perfumes/colognes, after-shave lotions, gargles/gargles and tone/irritation (brasters)/skin conditioners.

Other methods and materials for preparing formulations in a variety of forms are also described in Anthony L.L.Hunting (ed.), "A formulation of cosmetic preparations (Vol.2) -Creams, localities and mills," Micell Press (England, N.J., 1993). See, e.g., chapter 7, pages 5-14 (oils and gels); chapter 8 pages 15-98 (bases and emulsions); chapter 9 pages 101-120 ("all-purpose products"); chapter 11, page 185-208 (foundation, vanishing cream and day cream); chapter 12, page 209-; chapter 13 297-; chapter 14, 325 and 380 (hand protection products); chapter 15 381-460 (body and skin creams and lotions); and chapter 16,461 and page 484 (baby products).

The compositions and formulations disclosed herein may also be incorporated into other articles of manufacture for use. For example, the compositions of the embodiments described herein may be incorporated into bandages to increase wound healing and reduce subject discomfort. The composition can be mixed with salt and chemotherapeutic agent in an intravenous drip bag. Methods for incorporating the ROM production and release inhibiting mixture into a wound dressing will be apparent to those of ordinary skill in the art. A discussion of the incorporation of actives into wound dressings is found in U.S. patent No.5,116,620.

Administration of the Compounds by injection

The compounds disclosed herein can be administered by injection. Specific modes of presentation include use of intravenous anastomotic shunts, hypodermic syringes, intravenous drip bags, intramuscular injections, intraperitoneal (intraperitoneal) injections, suppositories, inhalants, aerosol inhalants, transdermal uses, injectors, sponges, sprays (including medication, aerosols and bubbles, foam sprays), drip uses, sprays, salves, soaks, and gargles or mouthwashes.

Controlled release carriers are also useful for administering preferred embodiments of the compounds described herein. Techniques and product variations in the art may be referred to as controlled release, sustained release, prolonged action, depot, delayed action, retarded release, and timed release; the term "controlled release" as used herein means a combination of the various aforementioned techniques.

Many controlled release carriers are known, including biodegradable or bioerodible polymers such as polylactic acid, polyglycolic acid, and regenerated collagen. Known controlled release drug delivery devices include creams, lotions, tablets, capsules, gels, microspheres, and liposomes. Transdermal formulations from which the active ingredient is slowly released are also well known and may be used with the various embodiments described herein.

Controlled release formulations can be obtained by complexing or absorbing histamine using polymers. This controlled presentation can be carried out by selecting appropriate macromolecules such as polyesters, polymeric amino acids, polyvinylpyrrolidone, ethylene vinyl acetate, methylcellulose, carboxymethylcellulose, and protamine sulfate, and selecting the concentration of these macromolecules and the method of incorporation to facilitate controlled release of the active compound.

Hydrogels, in which the histamine compound is dissolved in an aqueous component to be gradually released over time, may be prepared by copolymerization of hydrophilic monoolefinic monomers such as ethylene glycol methacrylate. A matrix device may be used in which histamine is dispersed in a matrix of carrier materials. The carrier may be porous, non-porous, solid, semi-solid, permeable or impermeable. In addition, devices containing a central reservoir of histamine surrounded by a rate controlling membrane may be used to control the release of histamine. The rate controlling membrane comprises an ethylene vinyl acetate copolymer or a butylene terephthalate/polytetramethylene ether phthalate. The use of silicone rubber reservoirs is also contemplated.

Oral controlled release formulations are also well known. The active compound is dissolved or erodible in a matrix. Hydrophilic resins such as hydroxymethylcellulose are commonly used. Lubricants such as magnesium stearate, stearic acid or calcium stearate may be used to aid the tableting process.

In a preferred embodiment, the method of administration may be either local or systemic injection or infusion. Other methods of administration are also suitable. These compounds may be administered intraperitoneally or in another parenteral manner. Solutions of the active compounds in free acid or pharmaceutically acceptable salt form can be administered in water with or without a surfactant such as hydroxypropylcellulose. A dispersant using glycerin, liquid polyethylene glycol or a mixture thereof with oil may be used. An antibacterial agent may also be added to the preparation.

Injections may include sterile water-based solutions or dispersions and powders that may be dissolved or suspended in the sterile media used previously. Carriers such as solvents or dispersants containing, for example, water, ethanol polyols (ethanolpolyols), vegetable oils, etc., may also be added. Coatings such as lecithin and surfactants may be used to maintain proper fluidity of the formulation. Isotonic substances such as sugars or sodium chloride may also be added, as well as products intended to slow the absorption of the active ingredient such as aluminum monostearate and gelatin. Sterile injectable preparations are prepared in a conventional manner and filtered prior to storage and/or administration. Sterile powders are vacuum dried or freeze dried from a solution or suspension.

Nebulizer therapy, a nebulizer or an inhaler may be used to administer the formulation. The liquid fine mist of the formulation can be administered alone or in combination with an infection-specific chemotherapeutic agent to treat respiratory infections.

Eye drops and eye ointments may be used for administration of the formulations of the embodiments of the present invention. The formulation may be delivered by instillation, alone or in admixture with additional infection-specific chemotherapeutic agents. Eye ointments containing the formulations of the embodiments with or without antimicrobial, antiprotozoal, antiparasitic, or antifungal agents are administered to the eye, for example, while sleeping, to prolong exposure.

Surgical implants are designed to contain the formulations described herein. For example, dental implants that release the embodiment compounds over time are used to reduce inflammation of the gums due to tooth decay. In addition, the compositions described herein are mixed with antibiotics or antiseptics that inhibit the growth of streptococci in the oral cavity. The surgical device may be implanted along the gingiva near the center of the cavity or attached to the surface of the tooth.

Suppositories and enemas containing the formulations described herein are implanted in the affected area to reduce the body's inflammatory response to the infection. The formulation may be presented by suppository alone or in combination with other chemotherapies. For higher levels of microbial infection in the human gastrointestinal tract, enemas are suitable for presentation of the formulation alone, or in addition to other chemotherapy.

Intravenous administration of the formulations described herein is presented by injection into the bloodstream, muscle, peritoneal cavity, individual infected organs or organ systems, bone, lymphatic cavity, spinal cavity, sinus cavity, etc., alone or in combination with other chemotherapies specific for the infection intended to be treated.

In another preferred embodiment, transdermal patches, homeostatic reservoirs sandwiched between an impermeable backing layer and a membrane front, and transdermal formulations, may also be used to present histamine and histamine agonists. Transdermal delivery systems are well known in the art. Occlusive transdermal patches for administering active ingredients to the skin or mucosa are described in U.S. Pat. nos. 4,573,996, 4,597,961, and 4,839,174. One type of transdermal patch is a polymer matrix in which the active agent is dissolved and through which the active ingredient diffuses to the skin. These transdermal patches are disclosed in U.S. Pat. nos. 4,839,174, 4,908,213, and 4,943,435.

Current transdermal patch systems are designed to deliver smaller doses over longer periods of time, up to days and weeks, however, the embodiments described herein will specifically release an effective amount of histamine in a range of between about 1 and 60 minutes depending on the dose, with a preferred dose being released in about 5 minutes. These patches allow for rapid and controlled release of histamine. These patches are sized for direct placement on warts, wounds, herpetic lesions, foci of infection, and the like. Rate controlling outer microporous membranes, or fine histamine (micropockets of histamines) dispersed throughout a silicone polymer matrix, can be used to control the release rate. This speed control method is described in U.S. Pat. No.5,676,969. In another preferred embodiment, histamine is released from the patch into the skin of the patient in about 30 minutes or less. In a preferred embodiment, histamine is released from the patch at between about 0.025mg and 0.3mg per minute for a dose of between about 0.2mg and 3mg per patch.

The use of these transdermal patches and formulations may be with or without the use of permeation enhancers such as dimethyl sulfoxide (DMSO), sucrose fatty acid esters in combination with sulfoxide or phosphorous oxide, or eugenol. The use of an electrolytic transdermal patch is also within the scope of the embodiments. Electrolytic transdermal patches are described in U.S. Pat. nos. 5,474,527, 5,336,168, and 5,328,454.

In another embodiment, a transdermal patch designed to be placed on a wound, or wart, abrasion, injury, or infectious focus may be used to administer the active ingredients of the embodiments. Examples of such patches are found in U.S. patent No.5,122,127. The patch comprises a container capable of holding a quantity of therapeutic agent, the container being capable of adhering to mucosal tissue, for example in the oral cavity. The drug surface area of the device represents the mucosal tissue that contacts the host. The device is designed to release the drug in proportion to the size of the drug/mucosal interface area. Therefore, the drug release rate can be adjusted by changing the size of the contact area.

The container is preferably constructed of a material that is non-toxic, chemically stable, and non-reactive with the compounds of the embodiments described herein. Suitable constituent materials include: polyethylene, polyolefins, polyamides, polycarbonates, vinyl polymers, and other similar materials known in the art. The container may include means for maintaining the relative position of the container and the mucosa. The container may contain a steady-state reservoir of drug in a fixed position to maintain fluid contact with the mucosa.

The steady state reservoir used with the described embodiments will release the appropriate dose of these compounds throughout a pre-set time. Compositions and methods of producing compositions capable of absorption through the mucosa are taught in U.S. patent No.5,288,497. One skilled in the art can readily know how to include the compounds of the embodiments described in these and related compositions.

The steady state reservoir for the embodiments is comprised of compounds known in the art to control the rate of drug release. In one embodiment, the transmucosal patch releases a dose of histamine over a period of about 2 to 60 minutes. The steady state reservoir contained within the container carries histamine and other ROM production and release inhibiting compounds in doses from about 0.2 to 5mg per patch. Transdermal patches capable of being used for several days and releasing the compounds of the embodiments over this period of time are also contemplated. The depot may also contain penetration or penetration enhancers, as described above, to enhance the permeability of the active ingredient of the embodiments across mucosal tissue.

Another method of controlling histamine release incorporates histamine into particles of polymeric materials, such as polyesters, polyamino acids, hydrogels, polylactic acid, or ethylene vinyl acetate copolymers.

Alternatively, instead of incorporating histamine into these polymeric particles, histamine is embedded in microcapsules prepared, for example, by coacervation techniques, or by interfacial polymerization, for example, using hydroxymethylcellulose or gelatin microcapsules, respectively, or in colloidal drug delivery systems, for example, liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules, or in macroemulsions. Such techniques are well known to those of ordinary skill in the pharmaceutical sciences.

In another embodiment, histamine, H₂-the receptor agonist is administered at a total concentration of about 0.0001 to about 0.5% by weight of the formulation, more preferably about 0.001 to about 0.01% by weight of the formulation, and most preferably about 0.002 to 0.05% by weight of the formulation. The ROM scavenging compounds can also be administered in combination with ROM production and release inhibiting compounds as described above.

Administration of each dose of histamine may be from once a day to about twenty times a day, with five times a day being preferred. In addition, the compounds, compositions and formulations of the embodiments may be administered in suitable amounts or to an extent that the subject's pain or discomfort is alleviated. Hourly administration is also contemplated, however, administration should not exceed 20 times per day.

Administration of the compounds of the embodiments described herein may be alone or in combination with other compounds effective in the treatment of various medical conditions encompassed by the embodiments described herein. For example, histamine in combination with other compounds such as cefazolin may be used to treat patients afflicted with a klebsiella infection to alleviate discomfort in the subject while removing the body's infectious agents. In addition, the embodiments may be used with a variety of antibacterial, antifungal, antiprotozoal, and antiparasitic compounds known and administered to those skilled in the art. The compounds of the embodiments, such as a, may also be administered with various analgesics, anesthetics, or anxiolytics to increase patient comfort during treatment.

Administration of each dose of the compound that causes histamine release may be once a day to about ten times a day, with five times a day being preferred. In addition, the number of administrations may be as required by the subject to alleviate discomfort from an infected site, wound or skin wound. Administration encompasses injections, oral, inhalants, suppositories, or topical drugs and may incorporate controlled release mechanisms of the type disclosed above. Any controlled release carrier capable of administering a therapeutically effective amount of a compound that induces the depot release of endogenous histamine can be used.

Administration of ROM production and release inhibiting compounds by injection in combination with topical administration of these compounds is also contemplated. The administration of these compounds is taught in the co-pending application entitled "treatment and prevention of reactive oxygen metabolite-induced cell damage".

One of the surprising discoveries of the described embodiments of the invention is that compounds that reduce the amount of production or release of ROMs from a source in a subject can facilitate the treatment and recovery of individuals afflicted with a variety of medical conditions. These diseases encompass diseases caused by a large number of etiologies that are treatable within the embodiments. However, they share the common feature that their pathological state is caused or exacerbated by enzymatically produced ROM-mediated oxidative damage caused by inappropriate or harmful concentrations of ROMs. Thus, the administration of compounds that inhibit the production or release of or scavenge ROMs, alone or in combination with other beneficial compounds, provides an effective treatment for a variety of medical conditions.

The embodiments of the present invention encompass compounds and methods effective in the treatment of a variety of medical conditions in which the ROMs serve a motile, deleterious role in the pathological state of the disease.

All materials added to the formulation must be pharmaceutically acceptable and sufficiently non-toxic in the amounts used. Formulations and forms that produce delayed release are also part of the invention.

The formulations provide dosage units in a uniform dose and are convenient to administer. Each dosage unit contains a predetermined amount of active ingredient together with the necessary amount of pharmaceutical carrier to produce the desired therapeutic effect.

Although in the examples it is stated that administration is in a single dose, it is clear that the compound can be dispensed for a longer period of time for the treatment of bacterial, fungal, protozoal, parasitic or other parasitic infections which cause inflammation.

The daily dose may be administered as a single dose, or it may be divided into several doses if side effects occur.

These diseases include, but are not limited to: bacterial infections, fungal or yeast infections, protozoal infections, amoebic infections and parasitic infections. Many of the following have been or will be resistant to contemporary chemotherapy treatment. Therefore, in view of the following, it should be noted that the susceptibility to chemotherapy should be specifically analyzed for any particular cause of infection in order to effect the most appropriate treatment for the patient. Moreover, each microbial infection may be susceptible to several classes of chemotherapeutic compounds.

Pneumocystis carinii infections were treated with atorvastatin suspension or dapsone with trimethoprim or pentamidine. See, Antimicrobial Use Guidelines; university of Wisconsin Hospital 8^thEdition June 1996. Clindamycin is used for treating infection of Bacteroides fragilis (Bacteroides fragilis) and Staphylococcus aureus (Staphlococcus aureus) and aerobic gram-negative bacillus. See Young and Mangum, NeoFax, 8th Edition, 1995, page 18. Metronidazole is used to treat bacteroides fragilis, bacterial vaginosis, trichomonas vaginitis (trichomonas vaginitis), giardiasis, clostridium difficile colitis, entamoeba histolytica and helicobacter pylori infection. See Rollo IM: miscellaneous drugs used in the treatment of prozoalinfections, In: gilman AG et al, the pharmaceutical Basis of therapeutics 6th ed, MacMillan Publ, New York, 1980. p.1077. In addition, H.pylori is generally treated with amoxicillin, clarithromycin, tetracycline and metronidazole. See Physicians' Desk Reference 58ed.2002, Medical Economics/Thomson Healthcare p.1471-1474, 403-. Mycobacterium leprae and mycobacterium avium (m.avium) are treated with clofazimine. See National Institutes of Health (NIH), Warren GrantMagnus Clinical Center (CC) pharmaceutical Department, Bethesda, Maryland 20892.

Helicobacter pylori causes chronic gastritis in humans, often accompanied by life. The immune response of the host to H.pylori infection is generally characterized by massive infiltration of the stomach's upper subcutaneous lamina propria by phagocytes, mainly monocytes/macrophages and neutrophils, and lymphocytes, including cells that mediate protection against infection, such as Natural Killer (NK) cells and T cells.

Nitrofurantoin is used for treating urinary tract infection. See PDR2002, p.2891-2892. Crisp binuclear amoeba and cryptosporic diarrhea were treated with paromomycin. See Clin Infect Dis 1992; 15: 726; am J Med 1996; 100: 370. neisseria gonorrhoeae is treated with spectinomycin. See U.S. national Library of Medicine, 8600 Rockville Pike, Bethesda, MD 20894. Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae and Enterobacter species are generally treated with trimethoprim. See PDR2002, p.2265-2267. Vancomycin is also used to treat penicillin (methicillin) resistant staphylococcus aureus, clostridium difficile and corynebacterium infections. See PDR2002, p.1970-1978.

The following types of infections have been treated with β -lactam chemotherapeutics aztreonam has been used to treat severely aerobic gram-negative bacilli, see PDR2002, p.1276-1279 cefmetazole has been used to treat soft tissue infections, bone infections and infections caused by penetrating abdominal trauma, see antipicrobial Use guidelities, origin Edition, University of wisconsin Hospital, June 1996 chlorocarba (Loracarbef) is used to treat acute otitis media and sinusitis, see PDR2002, p.2251-2254 imipenem and cilastatin is used to treat pseudomonas aeruginosa, enterobacter, serratia or citrobacter infections, see PDR2002, p.2158-2164.

Ampicillin (amoxicillin) has been found to be useful for the treatment of acute otitis media, bacterial endocarditis prophylaxis and enterococcal infection see PDR2002, p.1471-1474 ampicillin is found to be useful for the treatment of Escherichia coli, Proteus mirabilis, enterococcal endocarditis, neonatal meningitis, Listeria meningitis/sepsis, Haemophilus influenzae, miningitis, Shigella dysentery, Salmonella diseases or typhoid, antibiotic Using Guidelides, 8th Edition, University of Wisconsin Hoital, June 1996. amoxicillin and Clavicornic acid are found to be useful for the treatment of otitis media and acute sinusitis see PDR2002, p.1471-1474 and 1482-cottonin 0. dicloxacillin is found to be useful for the treatment of penicillin-resistant, penicillin-sensitive staphylococci, such as Escherichia coli, Escherichia coli infection, Escherichia coli infection with Streptococcus pyogenes, Escherichia coli infection with Escherichia coli, Escherichia coli infection with Escherichia coli.

Malaria caused by plasmodium vivax, plasmodium malariae, plasmodium ovale and plasmodium falciparum sensitive strains is specifically prevented and treated by chloroquine phosphate. The drug family called sulfa drugs is used to treat the following infections. Chloroquine-resistant plasmodium falciparum is treated with sulfadiazine, quinine and pyrimethamine. See Goldsmith, R.S., Antiprozoal drug Basic and pharmaceutical Pharmacology (Katzung, B.G., ed.) Appleton-Lange, 1998, pp.838-861. Trimethoprim in combination with sulfamethoxazole is used for the treatment of urinary tract infections, acute prostatitis, pneumocystis carinii, shigella dysenteriae, typhoid fever, enteropathogenic escherichia coli, traveller's diarrhea, stenotrophomonas maltophilia (stenotrophomonamalphilia), burkholderia cepacia, neopenicillin-resistant staphylococcus aureus and atypical mycobacterial infections. And Id.

Methicillan Resistant Staphylococcus Aureus (MRSA) is a staphylococcus resistant to neopenicillin and other common antibiotics, and they have unique genes that produce resistance. Therefore, MRSA must be treated with a backup antibiotic. Of these antibiotics, vancomycin is the most effective and reliable. See Koren et al, J pens, V110N 5, p.797, May 1987, Benitz & Tarro, Petridatric Drug Handbook, p.571, 1988, Leonard et al, Ped Inf Disease J.V8N 5, p.282, May 1989 Yeh, Neonatal therapeutics, 2nd Ed, p.198, 1991.

The following microbial infections have been found to be sensitive to chemotherapy of the so-called tetracycline family. See Ziv & sun, am.j.vet.res.35: 1197, 1974.USPDI, 11th edition, 1991USPDI, 15th edition, 1995 BM6th88, Huber, W.G., Tetracyclines, in Veteriary Pharmacology and Therapeutics, 6th edition, eds. Booth, N.H.and McDonald, L.E., Iowa State University Press, 1988.Rang, H.P.and M.M.Dale. Pharmacology, Churchill Livingstone, New York 1987, channel 30.Bowersock, T.1995. Personal bacterium. Minocycline is used for the treatment of neisseria meningitidis and mycobacterium marinum. Tetracycline is useful for the treatment of mycoplasma pneumoniae and chlamydia trachomatis. And Id.

Cefazolin is used for treating Klebsiella or Escherichia coli pneumonia or wound infection. See Harriet Lane Handbook, p.619, 2000.CHLA peptide diagnosis Handbook and formality, p.182, 1999. Neoneal medicines and treatment, p.90, 1999. cefixime is used for the treatment of penicillin resistant species of gonorrhea, acute sinusitis and acute otitis media. See Girgis NI, Kilpatrick ME, Farid Z, et al: drug Exp Clin Res 1993, center in the treatment of experimental farm in children; 19: 47-49; johnson CE, Carlin SA, Super DM, etal: cefixime shared with amoxicillin for processing of accessibility media.J Pediatr 1991; 119: 117-122 cefpodoxime proxetil is useful for the treatment of sinusitis. See PDR2002, p.2860-2864. pseudomonas aeruginosa was treated with ceftazidime. Id.at 1499-. Streptococcus pneumoniae, Haemophilus influenzae (Branhamella), Moraxella catarrhalis, staphylococci and streptococcal skin infections, prostatitis caused by Escherichia coli, Proteus mirabilis and Klebsiella bacteria were treated with cephalexin. Id.at 1237-.

So-called fluoroquinolones are used for the treatment of the following infections. Neisseria meningitidis, Pseudomonas aeruginosa, Salmonella chaperones, Shigella, Campylobacter or enteropathogenic Escherichia coli severe intestinal infections and gram negative osteomyelitis were treated with ciprofloxacin. See PDR2002, p.893-903. Neisseria gonorrhoeae, non-febrile traveller's diarrhea, chronic prostatitis are included in infections treated with norfloxacin. Id.at 2051-.

Toxoplasma gondii is the cause of toxoplasmosis and is treated with pyrimethamine and sulfadiazine. See PDR2002, p.1511-1512 and cdc, availability of sulfadiazine-United states, mmwr 1992; 41: 950-1.

Mycobacterium avium complex, penicillin-resistant Streptococcus pneumoniae were treated with clarithromycin. See PDR2002, p.403-411. Infection with chlamydia trachomatis, mycoplasma pneumoniae, legionnaires' disease, chlamydia pneumoniae, campylobacter jejuni, bordetella pertussis, haemophilus ducreyi, acne vulgaris and corynebacterium diphtheriae is treated with erythromycin. Id.at 455-.

Aminoglycosides are used to treat the following microbial infections. Mycobacterium avium complex and drug-resistant tuberculosis are treated with amikacin. See Young and Mangum, NeoFax, 8th Edition, 1995, page 4. Isoniazid, rifampin and ethambutol for tubercle bacillusPyrazinamide and streptomycin treatment. See Core Currickulum on Tuberculosis What the Clinician Should Know 4th. Ed., 2000. streptomycin is also used for the treatment of streptococcal endocarditis. See U.S. environmental Protection agency, 1988.fact SheetNumber 186 streptomycin.usepa.washington, dc. tobramycin for the treatment of pseudomonas aeruginosa. See McCracken and Nelson, antibiotic Therapy for Newbones, 2nd Edition, 1983, Benitz&Tarro, Petric drug handbook, p.510, 1988 enterococcal endocarditis was treated with gentamicin and penicillin. See, antibiotic Use Guidelines, University of Wisconsin Hospital 8^th edition，June 1996.

The following antifungal agents were used to treat the respective fungal infections. Griseofulvin is used for treating dermatophytosis (tinea) of skin, hair, and nails (tinea corporis, tinea barbae, tinea capitis, and tinea unguium). See E Haneke, I Tausch, M Brutigam et al, short-duration apparatus of finger tissue degradation: see Journal of the American academy of Dermatology 199532: 72-7. Miconazole is used for the treatment of pseudomycosis boides and malassezia furfur systemically. See PDR2002, p.2661-2662. Amphotericin B is used to treat argyrobacter capsulatus (i.e., histoplasma capsulatum), argyrobacter dermatitis (i.e., blastomycosis dermatitis), candida profunda infections, and conidiophora casei is treated with amphotericin B. See Benitz & tarro, Pediatric Drug Handbook, p.621, 1988.Medical Letter, February 21, 1992. candida infections, including urogenital and oral candida albicans infections, were treated with nystatin, amphotericin B or fluconazole depending on the site of infection. See Harriet Lane Handbook, p.161, 1975 Sims, Metal: functional inorganic and functional additives in-low-birthweight additives, am J surfactants 5 (1): 33, January 1988 cryptococcus was treated with amphotericin B or fluconazole. See Cooper CR Jr, McGinnis MR. Invitro Suceptibility of clinical yeast isolateto fluconazole and terconazol. am J Obstet Gynecol 1996; 175: 1626-31. Aspergillus infection is treated with amphotericin B or itraconazole. See Drake LA, Dinehart SM, Farmer ER, Goltz RR, Graham GF, et al, guidelines of care for superficial mycoses infections of the skin: onychomycosis.j Am Acad dermaltol.1996; 34: 116-21 coccidioidomycosis is treated with amphotericin B or ketoconazole. See PRD 2002, p.2008-2009.

Typically, bacteroides, prevotella, clostridia, bifidobacterium, Bilophila, campylobacter, centripeda, escherichia, eubacteria, clostridia, twins, haemophilus, lactobacillus, Mitsuokella, neisseria, digestive streptococci (peptococcus streptococci), porphyromonas, propionibacteria, proteus, pseudomonas, sarcina, cresomonas, rottenna (Serpula), staphylococcus, streptococcus, veillonella, anaerobes of the genera woliniella, and most gram-positive anaerobes use one or a combination of clindamycin, metronidazole, cefixone, doxycycline, amoxicillin, or β -lactamase inhibitors, see PDR2002, p.1405-1406. for most gram-negative anaerobes, treatment is typically done with piperacillin or tobramycin and bactetabactam, poison, inc.

For example, the causative streptococcus pyogenes (also known as flesh eatingbacillia) of necrotizing fasciitis is treated with one or more of the following: a cephalosporin; erythromycin; penicillin; clindamycin; and vancomycin. See Dellinger EP, Severe necrotizing soft-tissue infections, JAMA 1981; 246: 1717-1720.

Absidia infections are associated with high mortality rates, especially in critically ill patients. The fungus often enters the body through the respiratory tract or passes directly to abraded skin. The main sites of infection are the sinus cavities, lungs, skin, gastrointestinal tract and central nervous system. Polyenes, mainly amphotericin B, flucytosine and diazadiene pentacycles, are major antifungal agents useful in the prevention and treatment of such fungal infections. See Bennett, J.E. functional innovations (Section 15: Infectious diseases), In Harrison's Principles of Internal Medicine 14, Isselbacher, K.J., and Braunwald, E.S., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds.) McGraw-Hill, Inc. (health Processes division), 1998, pp.1148-1163.

Certain species of the genera Gliocladium freudenreichii and Acanthamoeba are commonly found in lakes, swimming pools, tap water, and heating and air conditioning units. Although only one resistant grignard is known to infect humans, several acanthamoebae are implicated, including a.culbertsoni, a.polyphaga, acanthamoebae, a.astrronyxis, a.hathetetti and a.rhysodes. Other factors of the human disease balamuthia andrillaris involve leptomoxid ameba. Acanthamoebae enters the eye through a lens or through a corneal incision or wound. Resulting in infection or corneal ulceration. In addition, certain species of acanthamoeba may cause skin damage and/or systemic (systemic) infections. Topical application of 0.1% diamidinodiphenoxypropane isethionate plus neomycin-polymyxin B-gramicidin ophthalmic solution is generally considered an effective treatment. See The Pharmaceutical Journal, Vol 264 No7082 p212-218 (Feb.2000). Keratoplasty is often necessary for severe infections. Although most cases of brain (CNS) infection with acanthamoeba lead to death, patients recover from the infection with appropriate treatment. In addition, new cases of acanthamoebae, which established cases to respond to sulfonamides, are often treated with amphotericin B. See De Jonckheere JF: ecology of Acanthamoeba.Rev infection Dis 1991 Mar-Apr; 13 Suppl 5: s385-7; martinez AJ: (iii) Infection of the central nervous system product to Acanthhamoeba. Rev Infection Dis 1991 Mar-Apr; 13 Suppl 5: s399-.

Mycoplasma species, two kinds of acholeplasia (Acholeplasma) and one kind of ureaplasma were isolated from humans. See Goodman and Gilman (9th Edition), Chapter 49, pp.1175-1188; the six urogenital areas are the major sites of transplantation, but other species with oropharynx and respiratory tract as the major sites are sometimes found in the urogenital tract due to contact with the orogenital tract (orogenic). Polyene antibiotics are commonly used in therapy. However, their action must be closely observed, since the drug acts on cholesterol found on (act against) mycoplasma membranes, they can also act on the plasma membrane of human host cells. And Id.

The genus Achromobacter includes the following species: anitratus, baumann, cytinovorum, lwoffi, putrefaces, xylosidases. This is a gram-negative, aerobic, motile genus of bacteria that occurs in water and soil. Some are common inhabitants of the vertebrate intestinal tract. These bacteria sometimes cause opportunistic infections in humans. They can be treated with chloroquinolone, piperacillin or an aminoglycoside in combination with ceftazidime or pefloxacin. See PDR2002, p.1499-1502.

In recent years, acinetobacter species have emerged as clinically important pathogenic bacteria. Although these organisms are widely prevalent in nature, most human infections are nosocomial. Acinetobacter baumannii is the main species. See Hsueh P-R, et al, pandrun-resistant Acinetobacter baumannii occupying nosocomial infections in organizational hot, Taiwan, Emerg Infect Dis (Aug. 2002). Hospital acinetobacter baumannii infections such as respiratory tract infections, urinary tract infections, post-neurosurgical meningitis, and bacteremia mainly affect serious potential patients in hospital intensive care units and are often in-hospital outbreaks. Combination chemotherapy methods are often used to treat this type of infection. And Id.

Endocarditis caused by HACEK microorganisms (haemophilus parainfluenzae, haemophilus haliotidis, actinobacillus actinomycetemcomitans, cardiobacterium hominis, achnatrocarbides and rigobacterium aurantiaca) can be treated with cefiaxone sodium, ampicillin sodium and gentamicin sulfate. See Young and Mangum, NeoFax, 5th Edition, 1995, page 14.

Actinomycetes, including species causing human infections such as dentrolns, erksonii, georgiae, gerensceriae, hordeovoris, howellii, Actinomyces israeli, Actinomyces mairei, Actinomyces naeslundii, Actinomyces carinata, Propionicus, biogenes, ramosus, slackii, Actinomyces viscosus are treatable with minocycline. See Newman, m.g.; kornman, k.: Antimicrobial/Antimicrobial Use in dentalppractive-Chapter 11, 136-147, Quintes Sence, 1990.

Aerobacter aerogenes, escherichia coli, various proteus species, aerobacter genus, klebsiella genus, shigella genus, and salmonella genus cause acute and chronic urinary tract infection, cystitis, pyelonephritis, prostatitis, postpartum pyelonephritis, urethritis, and cystitis trigonitis. Intestinal infections can also be the result of salmonella, shigella, escherichia coli and proteus infections. An effective amount of nalidixic acid (quinolone) is administered to the patient to treat these gram-negative infections. See Kator, h.and m.rhodes.1994.microbial and chemical indicators.in: environmental Indicators and Shellfish safety, C.M. Hackney and M.D. Pierson, (Eds.) pp.30-91.Chapman and Hall Publishers, New York, NY.

Aeromonas, including the following species: aeromonas caviae, Aeromonas hydrophila, jandaei, media, Aeromonas salmonicida, Aeromonas mildus, tropa, veronii can cause wound infection. The antibiotic is selected from aminoglycosides, tribasic cephalosporin, imipenem, meropenem, aztreonam, trimethoprim-Sulfamethoxazole (SXT), tetracycline, chloramphenicol, and ciprofloxacin. See, Arias, et al, analytical systematic statistical analysis of Gram negative bacterial isolated from atomic feed Rev Biome.2000: 11; 169- & 174 gentamicin, SXT, ciprofloxacin and cephalosporins can be used for wounds containing these bacteria. See Altwegg M.1999 Aeromonas and Plesiomonas in PR Murray et al (ed.) Manual of clinical microbiology, 7^th ed.American Society for Microbiology，Washington D.C。

A preferred treatment for angiostrongylus cantonensis (eosinophilic meningitis) or angiostrongylus costatus (abdominal angiostrongylosis) infection is mebendazole. See also Department of Pathology, The Johns Hopkins Medical Institutions, Vol.15 No.12, Microbiology Newsletter, Monday, March 18, 1996. additionally, diethylcarbamazine, thiabendazole, and albendazole have been used to "alleviate" symptoms. However, surgery is often used to remove these nematodes from the body. See Barger, i.a.1992, control of organic chemicals haemonchus works hop, College Park, md. pyogenic actinomycete infections treated with antibiotics and surgical drainage wounds. Among all actinomycete infections, penicillin is the drug of choice. Actinomycetes, certain species and propionibacterium propionicum (p. propionicum) are often sensitive to penicillins, cephalosporins, tetracyclines, chloramphenicol and a variety of other antibiotics. And Id.

Cryptococcus haemolyticus for antibiotics other than penicillin and erythromycin is intermittent and based on routine disc diffusion experiments and a limited number of strains. McNeil MM, Brown JM.the Medium opportunity antigens: epidemic and microbiology clin Microbiol Rev 1994; 7: 357 and 417. it has been reported that S.haemolyticus is equally sensitive to clindamycin, chloramphenicol, cephalosporin and fusidic acid.

Ascariasis, also commonly referred to as "roundworm" infection and whipworm infection, and in particular gastrointestinal or biliary obstruction secondary to ascariasis, can be treated with piperazine citrate. The medicine can be used for treating parasite flaccid paralysis by blocking the reaction of parasite muscle to acetylcholine. Mebendazole is also useful in therapy. See Gilles HM: intellectual Nematode infestations, in GT Strickland, ed. Hunter's pharmaceutical medicine. Philadelphia: WB Saunders; 1984; 620, 644. this drug causes parasite death by selectively and irreversibly blocking the uptake of glucose and other nutrients in the gut of susceptible adults colonized by the parasite. Additionally, albendazole, mebendazole, and pyrantel pamoate are used to treat ascariasis. See Garcia, l.s.2001.diagnostic Medical parasitism, 4th ed., ASM Press, Washington, d.c.

Schistosomiasis is caused by amphoteric schistosomiasis. Three species that infect humans are schistosoma japonicum, and schistosoma mansoni. See Grove, D.I.and Warren, K.S.relationship of importance of interaction to distance in hamsters with access science society mansoni. American Journal of clinical medicine and Hygene 25: 608612, 1976 the drug of choice is praziquantel for infections caused by blood fluke species. See Befidi Mengue, R.N.et al, (1993), Impact of Schistosoma haematobium infection and of praziquantel project organization of primary school child in Bertou, Cameroon.J. TropMed Hyg.96 (4): 225-30. in some areas infection by Schistosoma mansoni with less praziquantel effect is treated effectively with oxaliquine. See Brindley PJ. drug resistance to chemical compounds and other anti chemical entities, Acta Trop 1994; 56: 213-31.

Human yeast is a protozoan that is occasionally found in the human intestinal tract, and its pathogenicity is controversial. This microbial infection also occurs in other animals. Even if the clinical importance of this organism is controversial, metronidazole or diiodoquinoline have been reported to be effective. See Benitz & Tatro, Pediatric drug handbook, p.650, 1988, sensiars in Pediatric inf. 15-19, Jan.1994.

Comprises the following steps: human Aspergillus infections of Aspergillus flavus, Aspergillus fumigatus, Aspergillus glaucus, Aspergillus nidulans, Aspergillus niger, Aspergillus terreus can be treated with amphotericin B, itraconazole, granulocyte-macrophage colony stimulating factor. See Geissmann F et al. aspergillus brassieses: other options studied for the treatment of aspergillosis include lipofectin (liposomal) amphotericin B and pandiomycin (pradimicin), Therapeutic effect of G-CSF and liposomalamidotricin B.Abstract # PB0602, X Int Conf AIDS, Yokohama, 1994. Intranasal and aerosolized amphotericin B may have prophylactic effects to reduce nasal dose (carriage) in patients with delayed neutropenia. And Id.

Retransmission of babesia occurs by infected tick (dannini hard tick) bites, but infections caused by blood transfusions are also recognized. See Epideiologic Notes and reports Clindamycin and Quine Treatment for Babesia microti Infects CDC MMWR Weekly February 11, 1983/32 (5); 65-6, 72. infections can occur ranging from asymptomatic to severe life-threatening diseases with fever, chills and hemolytic anemia. Treatment of this disease can be accomplished with clindamycin and quinine. And Id.

Bacillus includes Hippocampus (alvei) anthrax, Bacillus brevis, Bacillus cereus, Bacillus circulans, Bacillus coagulans, duplexnoliquefasciens, firmus, Laterosporus, lenus, licheniformis, macerans, Bacillus megaterium, mycoides, Bacillus polymyxa, pumlus, spaericus, stearothermophilus, Bacillus subtilis, Thrungensis, see Turnbull PCB, Kramer JM, Melling J, Bacillus.p.187.in ParkerMT, Duerden BI (eds): Systematic Bacteriol. Topley and Wilson's copolymers of Bacteriology, Virology and immunity, Vol.2.Edward, and Virology, enteroaks, Engleglo, Engler & skin (1990) including food products derived from Bacillus anthracis, food poisoning, food.

The genus Bacteroides includes the following species: amylophilus, Asachrolyticus, BIVIUS, Buccae, Buccalis, Bacteroides coprocoides, Bacteroides hirsutus, cellulosollvens, corosories, corrodens, denicola, disies, distasonis, Bacteroides exsiccatus, endosatalis, forsythus, Bacteroides fragilis, Furcosus, Galactoronius, gingivalium, gracilis, hepanolyticus, hypomegagavage, intermedia, bacteroides lii, loeschii, macacaae, melanospodopsis, fadrobacterium, microfugus, microacidus, nodosurus, ochromis, orales, oris, lourus, bacteroides ovatus, peliophilus, prenophytophyllus, prenococcus, minovulgarus, succinogenes, rhodobacter sphaeroides, rhodo. While bacteroides are among the important sites in normal plants, they are also opportunistic pathogens, mainly in peritoneal infections. See Appelbaum PC, Spangler SK, Jacobs MR: susceptibility of 394 bacteria from, non-B. from group bacteria species, and Fusobacterium species to new antimicrobial Agents, antibiotic Agents Chemotherm 1991 Jun; 35(6): 1214-8 bacteroides fragilis is the most significant pathogen. Antibiotic treatment, including penicillin and clindamycin, has been found to be an effective treatment regimen in combination with abscess drainage and necrotic tissue removal. And Id.

Human infections including Bilophila wadsworthia are preferably treated with metronidazole, imipenem, chloramphenicol, or amoxicillin, ticarcillin, ampicillin or piperacillin in combination with β -lactamase inhibitors, in addition, the most effective treatment for such infections includes surgical drainage of abscesses and clearance of necrotic tissue, see Brook I: Pediatric and biological infection: diagnosis and management.2 nd.St Louis, Mo: Mosby, 1989.

The genus Bordetella includes the following species: bordetella ornithii, bronchicainis, Bordetella bronchiseptica, Bordetella parapertussis, Bordetella pertussis. Bordetella pertussis, the cause of pertussis (also known as whooping cough), is a very small gram-negative aerobic coccobacillus. See McCracken and Nelson, instantaneous therapy for Newboots, 2nd Edition, 1983, Benitz & Tarro, Pediatric drug handbook, p.559, 1988, Young and Mangum, NeoFax, 8th Edition, 1995, page 20, Janssens, J et al: "Improvement of compliance in diabetes surgery by Erythromycin," NEJM322 (15): 1028, April 12, 1990 an antibiotic that has been found to be effective in the treatment of pertussis infections is erythromycin. In addition, hospitalization and isolation is recommended for severely ill infants. And Id.

Lyme disease is an infection caused by the spirochete borrelia burgdorferi. This bacterium is transmitted to humans by the bite of deer ticks (sclerorhipicephalus) and western black foot ticks (hard pacific ticks). Several antibiotics are effective in the treatment of lyme disease. The presently preferred drug is doxycycline, a semi-synthetic derivative of tetracycline. Cefuroxime axetil and erythromycin can be used in patients allergic to penicillin or unable to take tetracycline. Advanced lyme disease, especially with objective neurological manifestations, can be treated with intravenous ceftriaxone or penicillin for 4 weeks or more as necessary depending on the severity of the disease. See barbeur ag.lyme Disease: the Cable, The Cure, The Controlysy.1996. The Johns Hopkins University Press, Baltimore, Md.

Moraxella catarrhalis (formerly known as Branhamella) is only found in humans. Presumably, it is spread from person to person. Once a person infects (acquires) the bacterium, it is often transplanted to that person without causing any immediate symptoms. And thereafter can become a systemic infection. Treatment of such infections is straightforward. A variety of antibiotics are effective against this organism. See Physicians' Desk reference. montvale, NJ: medical Economics Co; 2001.

brucella infections occur primarily through exposure to infected cattle or pigs, but also through consumption of milk that has not been autoclaved. Brucellosis is a systemic infection characterized by alternating fever, sweating and chills. Infections are carried by neutrophils to many body organs. McCracken and dNeelson, innovative Therapy for Newborn, 2nd Edition, 1983.Benitz & Tarro, Pediatric Drug Handbook, p.559, 1988.Young and Mangum, NeoFax, 8th Edition, 1995, page 20.Janssens, J et al: "Improvement of pathological expression in Diabetic gastropathies byErythromycin," NEJM322 (15): 1028, April 12, 1990 combination therapies, typically involving erythromycin, have been found to be effective. And Id.

Virtually all people infected with Campylobacter can recover without any special treatment. Species of campylobacter include: butzleri, cinaedi, campylobacter coli, consuss, cryarophilus, curvus, fennellae, campylobacter fetus, campylobacter dolphinus, campylobacter jejuni, campylobacter erythrocaudatus, aridis, campylobacter mucosae, mucosalislinis, campylobacter pylori, pyrisidis, recatus, campylobacter sputum, campylobacter uppsalae. As long as the diarrhea persists, the patient should drink large amounts of liquid. In more severe cases, antibiotics such as erythromycin or chloroquinolone may be used, which may shorten the duration of symptoms if administered early in the disease. And Id.

Cholera can be treated simply and successfully by immediately replenishing the body fluids and salts lost from diarrhea. The patient can be treated with an oral rehydration solution, a prepackaged mixture of sugar and salt, mixed with water and drunk in bulk. The solution is used throughout the world to treat diarrhea. Severe cases also require intravenous fluid supplementation. In the case of immediate rehydration, less than 1% of cholera patients die. See De S, Choudhuri a, Dutta P, Dutta D, De SP, Pal sc. doxycycline the treatment of cholera. bull WHO 1976; 54: 177-9.

Most of the pathologic manifestations of clonorchis sinensis are caused by inflammation and intermittent obstruction of the biliary tract. Praziquantel or albendazole have been found to be successful in treating such infections. See, Bounce P. Successfulture of Taenia saginata and Hymenolepsis na by a single dose of praziquantel. journal of the Egyptian Society of Parsitiology, 1991, 21 (2): 303-7.

Q fever is an infectious disease in animals caused by bernstein. Infection in humans often occurs by the inhalation of these organisms from the air containing the dry placental material of airborne infected herds, birthing fluids and faecal contaminated cowshed dust. Humans are often very susceptible to infection with the disease and very few organisms are required to cause the infection. In general, most patients can recover well within months without any treatment. However, in severe cases, a 100mg dose of doxycycline is administered orally 2 times a day for 15-21 days, a frequently prescribed treatment. See Bartlett JG, Dowell SF, Mandell LA, et al: guidelines from the sources of the Infect diseases Society of America. Clini Infect Dis.2000; a reported with permission of The University of Chicago Press.

The bacterial chlamydiae include the following species: chlamydia pneumoniae, chlamydia psittaci and chlamydia trachomatis, causing a range of diseases that infect from the eye, lungs and genito-urinary tract. Treatment of chlamydia is accomplished with a variety of antibiotics. Doxycycline is the antibiotic of choice because it is used for long-term treatment, can be taken with food, and is inexpensive. However, tetracycline, chloramphenicol, rifampin, and chloroquinolone may also be used. See MR Howell, TC Quin, CA Gaydos.screening for Chlamydia trachomations in asympttic womenn attaching attenuation clinics.Annals of Internal Medicine 1998128: 277-84.

The genera Escherichia, Klebsiella, enterococcus, Serratia and Citrobacter (collectively Coleus) and Proteus include the disclosed and opportunistic pathogens responsible for widespread infection. Many are normal intestinal flora. Coli (e.coli) is the most commonly isolated organism in clinical laboratories. Many antibiotics are the backbone of therapy.

The genus clostridium includes the following species: aerotolans, aldrich, argentinense, pasteurellum, clostridium beijerinckii, clostridium bifidum, clostridium botulinum, clostridium butyricum, clostridium cadaveri, carnis, celecoxscens, celluloformentans, clostridium, closteriforme, coccoides, coclauritum, cloinum, cyclindosporium, clostridium difficile, disparicum, torvus, ghoni, clostridium glycoluril, clostridium histolyticum, homoproprionium, indolium, clostridium innocuum, intestinalis, josui, lentellum, clostridium mucronatum, litorale, magnum, maleinum, methylpentosuum, nosylate, noscapinum, clostridium butyricum, clostridium phytofermentans, clostridium butyricum, clostridium purpureum, clostridium butyricum, clostridium purpureum, clostridium butyricum, clostridium purpureum, clostridium butyr. The infections caused by this genus of bacteria range from diarrhea, tetanus, botulism and gas gangrene. Treatment is successful in many cases due to the administration of an effective amount of oral vancomycin or metronidazole. See Pothoulakis, M.D., et al.division of Gastroenterology, Beth Israel deacess Medical center, Harvard Medical School, Boston MA., Participate (Fall2001).

Symptoms of cryptosporidium include diarrhea, loose or watery stools, cramps in the stomach, abdominal pain, and mild fever. One is asymptomatic, and infection continues as a carrier. See Petersen C.Cryptosporidiosis in tissues induced with the humanimobiochemical virus.Clin Infect Dis 1992; 15: 903-9 there is no established specific treatment for human cryptosporidiosis. The rapid loss of body fluids due to diarrhea can be controlled by replenishing body fluids and balancing electrolytes. Infection in healthy, immunocompromised persons is self-limiting, but infection in immunocompromised and less healthy persons is at higher risk of more severe disease. For AIDS patients, paromomycin has been used for treatment.

The cause of the circumsporosis (cyclosporinis) was only recently identified as the unicellular coccidia parasite, the perisporozoite kayana (cyclospora cayetanensis). It occurs in all human cases caused by this parasite. The recommended treatment for circumsporosis is a combination of two antibiotics, trimethoprim and sulfamethoxazole, also known as Bactrim, Septra or Cotrim. Supportive therapy includes resting and managing fluid and electrolyte balance. See Remington & Klein, Infections Diseases of the Fetus & Newborn, p.559, 1990, Benitz & Tarro, Pediatric Drug Handbook, p.576-7, 1988.

The taenia lata (the fish or branched tapeworm) of the subclass cestoideae is the largest human taenia. Several other schizocephala species have been reported to infect humans, but rarely; they include d.pacificum, cestodes cardioformans, d.ursi, d.dentriticum, d.lanceralatotum, d.dalliae and d.yonagoensis. This parasite was successfully treated with the drug praziquantel. See, Bounce P. Successfulture of Taenia saginata and Hymenolepsis na by a single dose of praziquantel. journal of the Egyptian Society of Parsitiology, 1991, 21 (2): 303-7.

The genus Corynebacterium includes the following species: corynebacterium aquaticum, Corynebacterium bovis, Corynebacterium diphtheriae, Corynebacterium equi, Corynebacterium haemolyticum, Corynebacterium jeikeium, Corynebacterium kuchensiei, Corynebacterium matrucchoti, Corynebacterium parvum, Corynebacterium pseudodiphtheriae, Corynebacterium pseudotuberculosis, Corynebacterium pyogenes, Corynebacterium reniformis, Corynebacterium striatum, Corynebacterium ulcerans, Corynebacterium urealyticum, Corynebacterium vesiculosum, and Corynebacterium siccatum. Corynebacterium diphtheriae has been treated with a diphtheria antitoxin against diphtheria toxin (counter), and an antibiotic against diphtheria, such as penicillin or erythromycin. See PDR2002, at p.2240-2243.

Enterobacteriaceae (clinically important enterobacteria) include: citrobacter freundii; citrobacter diversus; certain species of the genus enterobacter; enterobacter aerogenes; enterobacterragomers; enterobacter cloacae; e.coli; opportunistic (Opportunistic) E.coli; enterotoxigenic escherichia coli (ETEC); enteroinerivactive escherichia coli (EIEC); enteropathogenic E.coli (EPEC); enterohemorrhagic escherichia coli (EHEC); coli (eaggeec); uropatogenic E.coli (UPEC); klebsiella pneumoniae; acid-producing klebsiella oxytoca; morganella morganii; proteus mirabilis; proteus vulgaris; providencia; producing base providencia; providencia rettgeri; providencia stuartii; salmonella enterrica; salmonella typhi; salmonella paratyphi; salmonella enteritidis; salmonella choleraesuis; salmonella typhimurium; serratia marcescens; liquefying Serratia spp; shigella dysenteriae; shigella flexneri; shigella boydii; shigella soxhlet; yersinia enterocolitica; yersinia pestis and Yersinia pseudotuberculosis. Infections involving these bacteria are often treated with either aminoglycosides, chloramphenicol, or trimethoprim sulfamethoxazole. Cases of simple diarrhea caused by yersinia enterocolitica are usually eliminated on their own without antibiotic treatment. However, in more severe or complex infections, antibiotics such as aminoglycosides, doxycycline, trimethoprim sulfamethoxazole, or fluoroquinolone may be helpful. See Harrison's Principles of Internal Medicine 15th Ed. Chapter31, (2001).

Ciprofloxacin and fluoroquinolone are the drugs of choice for empirical treatment of the invasive and traveler's diarrhea syndrome in adult patients. They are also the drugs of choice when treatment is needed and the etiologies are known to be campylobacter, escherichia coli (non 0157: H7), salmonella-non typhoid (although antibiotic treatment can delay bacterial shedding), shigella and yersinia. Antibiotics commonly used for the treatment of shigellosis are ampicillin, trimethoprim/sulfamethoxazole, nalidixic acid or ciprofloxacin. See Litt JZ, Drug Erup Reference Manual, New York, Parthenon Publishing (2000).

Salmonella infections are often eliminated within 5-7 days and generally do not require treatment unless the patient is severely dehydrated or the infection spreads from the intestine. Patients with severe diarrhea may require rehydration, often with intravenous fluids. Antibiotics are not generally necessary unless the infection spreads from the intestine, and may be treated with ampicillin, gentamicin, trimethoprim/sulfamethoxazole, or ciprofloxacin. See PDR2002, at p.887-902.

Ehrlichiosis can be a serious disease, especially if untreated, and as many as half of patients require hospitalization. Severe manifestations of the disease may include chronic fever, renal failure, disseminated intravascular coagulation, meningitis, adult respiratory distress syndrome, seizures, or coma. The drugs used for treatment are often tetracycline antibiotics, such as doxycycline. See PDR2002, at p.2735-2738.

Treatment of Trypanosoma brucei infection should be initiated as soon as possible and based on the symptoms of the infected person and laboratory results. The drug treatment regimen depends on the type of infection and the stage of infection. Pentamidine ocite and suramin (according to the new drug protocol from the CDC drug service) are the first drugs of choice for the treatment of the hemolymphatic stage of west and east african trypanosomiasis, respectively. Mearsinol is the first choice for the late stage of the disease associated with central nervous system involvement. See Bryan R, Waskin J, Richarcs F, et al, African Trypanosomisis in American movers: track medicine Steffen R, Lobel HO, Haworth J, Bradley DJ, eds. Berlin: Springer-Verlag, 1989: 384-8.

The protozoan parasite, trypanosoma cruzi, causes trypanosomiasis nana, an infectious disease of animals that can be transmitted to humans by stinkbug. See Hagar JM, rahitoloa sh. chagas' heart disease. curr pro cardio 1995; 20: 825-924. Pharmacological treatment of echinococcosis is generally effective when administered during the acute phase of infection. The drug of choice is benznidazole or nifurolimus (according to the new drug test protocol from the CDC drug service). See Veloso, VM. et al. variational Suadaptability to Benznnidazole in Isolatetes Derived from tryptanosoma cruzi Paratalstrains Melmoris do institute to Oswaldo Cruz Vol.96 (7): 1005-1011, (Oct.2001). No drug treatment proved effective once the disease progressed to an advanced stage. In the chronic phase, treatment includes control of symptoms associated with the disease. And Id.

Streptomyces infections require long-term antibiotic therapy and surgical control. See McNeil MM, Brown jm. the medicality import aerobics actinomycetes: epidemiology and microbiology clin Microbiol Rev 1994; 7: 357-417. In vitro, S.somaliensis (somaliensis) is sensitive to rifampicin, erythromycin, tobramycin, fusidic acid and streptomycin. The strain is tested for trimethoprim resistance. For S.somali infections, treatment with sulfamethoxazole or dapsone and streptomycin is recommended. The average treatment period was about 10 months. And Id.

The metranolong, the guineawork, is usually treated by carefully removing the worm by winding it on a rod. However, chemotherapy therapies such as thiabendazole and metronidazole are also used. See WorldHealth Organization, Fact Sheet No.98 DrajuncliasisEradiction (March 1998).

Helminthic (roundworm nematode) helminthic enteromyxoides (formerly known as oxyuriversicularis) also known as pinworm, cause infections in humans. Their infection is treated by the use of a drug known as pyrantel pamoate. See RIM Han-Jong; antibiotic interference of antioxidant and pyridine surfactant aggregation and antibiotic ligands SO: Korean-J-Parasitol 1975 Dec; 13(2): 97-101.

Flukes, fasciola hepatica (sheep liver fluke) and fasciola gigantica are generally parasites of herbivores but occasionally infect humans. Unlike other fluke infections, fasciola hepatica infections may not respond to praziquantel. The drug of choice is triclabendazole, and thiochlorophene as a substitute. See World Health Organization, Fact Sheet No. 191Triclavendazole and Fascioliasis-A New Drug to Combat and Age OldDisase (April 1998).

Fasciolopsis, fasciolopsis brunetti, is the largest intestinal fasciolopsis in humans. The infection has been successfully treated with the drug praziquantel. See Brown and Neva, basic clinical parasitism (6th ed.), pp 217-.

Filariasis is caused by nematodes (roundworms) that inhabit lymphoid and subcutaneous tissues. Three of them are responsible for the majority of the morbidity attributed to filariasis: the B.bangiae and the D.malayi cause lymphatic filariasis, while the D.discilalis causes the disease of D.discilalis (river twining). The other 5 species are ocular filariasis, grandmanson nematode, Strongylon nematoda, Osmanthus austenitalis and Brugia timori (the last also causes lymphatic filariasis). See Hotez.P.J.et al.Emerging and reviewing Helminthoses and the Public health of Chinese Emerging in ingredients Diseases Vol.3, No.3(July-September 1993); gubler, D.J.Resurgent Vector-BorneDisasesa Global Health promotion DisaseVol.4, No.3(July-September 1998). antibacterial cream is used for wounds as a topical treatment for their infections. This treatment prevented bacterial infection and prevented the swelling from worsening. Ethiamine oxazine (according to the new drug protocol from the CDC drug service) and ivermectin are effective in treating filariasis.

Giardia lamblia, a protozoan flagellate (trichomonas order), can cause severe diarrhea infections in humans. Several prescription drugs are available for the treatment of giardiasis, however metronidazole is the drug of choice. See Hill dr. giardia. in: mandell GL, BennettJE, Dolin RD, editors, Mandell, Douglas, and Bennett's principal and practice of infectious diseases, 4th New York: churchlilllivingstone inc; p.2487-91.

Nematodes (roundworms) acanthagora infect vertebrates, including humans. Human jawbreaker disease is due to migrating larvae. Treatment with albendazole and concurrent surgical resection has been successful. See Garcia LS.practical Guide to Diagnostic diagnostics, Washington DC, American Society For Microbiology, 1999.Garcia LS and DA Bruckner.diagnostic diagnostics, 3rd edition.Washing DC, American Society For Microbiology, 1997.The Medical Letter On drivers and therapeutics, April 2002. drivers For Diagnostic Infections, Mark Absamowicz (Editor.) The Medical Letter driver, Inc.New roller, NY.

Broad spectrum cephalosporins and chloroquinanonones have been found to successfully treat simple genitourinary tract infections caused by neisseria gonorrhoeae. See The Merck Manual of Diagnosis and therapy, Sec.13 infection diseases, Ch.164 Sexually transmitted diseases (1995-2000).

Streptococcus pyogenes continues to be highly sensitive to β -lactam antibiotics, and several studies have demonstrated the clinical efficacy of penicillin preparations on streptococcal pharyngitis, see Sin, FP.et al, Aretro specific review of properties with a novel disinfecting facial presentation to an infectious disease removal in Hong Kong, Hong Kong journal of infectious disease Medicine Vol.9, No. l (Jan.2002). similarly, penicillin and cephalosporin have demonstrated efficacy in treating erysipelas, impetigo and cellulitis, all of which are most commonly caused by Streptococcus pyogenes.

Legionella can be found in many types of water systems. However, the bacteria multiply in large quantities in warm, stagnant water (90-105F.), such as legionella found in some plumbing and hot water tanks, cooling towers and evaporative condensers of large air conditioning systems, and whirlpool spas. See Legionella pneumophila infections, in: pickering LK, ed.red Book 2000; report of the Committee on Infections diseases.25th ed.American Academy of Pediatrics; 2000: 364-5 erythromycin currently recommended antibiotics for the treatment of patients with legionella. In severe cases, a second-line drug, rifampicin, may be used in addition to erythromycin. Other drugs may be used in patients who cannot tolerate erythromycin. And Id.

Leishmaniasis is a vector-transmitted disease caused by the obligate intracellular protozoan leishmania, transmitted by sand flies. See Boelaert M., et al, cost-effective of composing diagnostic-therapeutic strategies for visco-inflammatory modalities, Bull World Health Organ 1999; 77: 667-74 human infections are caused by infection of about 21 of 30 species of mammals. It includes 3 Leishmania donovani complexes (Leishmania donovani, Leishmania infantis, Leishmania donovani Chagas subspecies); leishmania mexicana (Leishmania mexicana, Leishmania mexicana amazoni subspecies); leishmania tropica; leishmania major; leishmania aethiopica; and 4 species of the subgenus vianna (brazil v. leishmania, yerana (guyanensis) v. leishmania, panama (panamensis) v. leishmania, peru v. leishmania). The treatment of infections caused by protozoa of this genus is sodium antimony gluconate. And Id.

Leptospirosis is a bacterial disease affecting humans and animals. It is caused by bacteria of the leptospira genus. See Radostics, O.et al, Verternary Medicine textbook of the Diseases of Catelle, sheet, Goats, Pics and Horses 8th Ed. London, Ballier Tindall, 1994884-. Symptoms of leptospirosis include high fever, severe headache, chills, muscle pain and vomiting, and may include jaundice (yellow skin and eyes), ocular congestion, abdominal pain, diarrhea or rash. If the disease is untreated, patients may develop kidney damage, meningitis (membrane infections around the brain and spinal cord), liver failure, and dyspnea. Leptospirosis is treated with antibiotics such as doxycycline or penicillin, which should be given early in the course of the disease. Intravenous antibiotics are required for more severe patients. And Id.

Head lice, an insect of the order pediculosis, is an ectoparasite whose only host is human. See Borror, d.j., c.a. triplehorn and n.f. johnson.1989.an introduction to the study of insects.6th ed.harcourt Brace, New york.p.875. lice feed on blood several times a day and inhabit near the scalp to maintain their body temperature. Treatment of their infections is often achieved by the application of topical drugs called pediculicides, while physically removing the lice from the host. And Id.

Listeriosis is a food-borne disease mainly caused by listeria monocytogenes. The most vulnerable persons to this disease are pregnant women, newborns, the elderly and patients with HIV or other immune-compromised diseases. Ampicillin alone or in combination with gentamicin has been the treatment of choice. See Calder, jennifer, "Listeria Meningitis in additives," Lancet 350 (1997): 307.

the term microsporidia is also used as a general nomenclature for obligate intracellular protozoan parasites belonging to the phylum microsporida. See Sandfort J et al, Albendazole molecular inhibitors with intracellular microsporidiosis Abstract PO-B10-1491, IX Intl Conf AIDS, Berlin, 1993 currently, over 1200 species belonging to 143 genera have been described as parasites infecting a wide range of vertebrate and invertebrate hosts. The first treatment for ocular microsporopathy induced by encephalitozolon hellem, intracerebral protozoa of rabbits or vitaformma coreane is albendazole plus topical fumagillin. Albendazole is the first choice for the treatment of intestinal infections caused by Encephalitozoon bienenus and Encephalitozoonintestinalis. And Id.

Rocky mountain spotted fever is the most severe and commonly reported rickettsia in the united states. See Archibald LK, Sexton DJ: long-term sequence of Rocky mountain installed feed, Clin Infect Dis 1995 May; 20(5): 1122-5. the disease is caused by rickettsia rickettsii, a bacterium transmitted to humans by hard (hard) ticks. The initial signs and symptoms of the disease include sudden fever, headache and muscle pain, followed by development of a rash. Treatment includes effective administration of doxycycline. And Id.

Trichomonas vaginalis, a flagellate, is the most common human pathogenic protozoa in industrialized countries. See Wolner-Hanssen P, Krieger J, Stevens CE, Kiviat NB, Koutsky L, Critchlorine C, et al, clinical evaluations of vaginaltrichionisis JAMA 1989; 261: 571-6. treatment should be performed under medical care and should include all sexual partners that infect patients. Id. the treatment preferred is metronidazole. Treatment is generally very successful. A well-tolerated alternative, tinidazole, is not available in the united states. However, Trichomonas vaginalis strains have been reported to be resistant to both drugs. And Id.

Sporotrichosis is a fungal infection caused by a fungus called schenckii sporotrichosis. See Ajello Land R.J.Hay.1997.medical Mycology Vol 4 Topley & wilson's Microbiology and infection infections.9th Edition, which commonly infects skin. Sporotrichosis is typically treated with potassium iodide and is administered orally in drops. A new drug known as itraconazole is available for treatment, but experience with this drug is limited. Treatment often exceeds several weeks until the lesion is completely healed. And Id.

Syphilis is a complex (STD) Sexually Transmitted Disease (STD) caused by the bacterium Treponema pallidum. See Centers for Disease Control and preservation, 1998 theoretical considerations for the treatment of sexualy transmitted diseases, MMWR 47 (RR-1): 1,1997, it is often referred to as a maximum simulator because very many signs and symptoms are indistinguishable from other diseases. One administration of the antibiotic penicillin cures patients with syphilis for less than 1 year. Patients with syphilis cured for longer than 1 year need multiple administrations. Id. infants born with this disease require penicillin treatment for 10 days. There is no family treatment or no prescribed medication to cure syphilis. Penicillin treatment will kill syphilis and prevent further damage, but it does not repair any damage that has occurred. And Id.

Toxoplasma gondii is a protozoan parasite which infects most species of warm-blooded animals, including humans, causing toxoplasmosis. See Torres, g.toxoplasmosis: new treatment Advances The gain Men's Health Crisis Newsletter of Experimental AIDS Therapies; volume 5 Number 3(mar.28, 1991) treatment is not required for healthy people who are not pregnant. Symptoms typically disappear within a few weeks. For pregnant women or patients with weakened immune systems, pyrimethamine plus sulfadiazine leucovorin is an effective treatment. And Id.

Trichinosis is caused by trichinella nematodes (roundworms). In addition to the classical etiology of trichinella spiralis (found in many meat and omnivorous animals worldwide), other 4-species nematodes are now recognized: pseudospiralis (mammals and birds worldwide), t.nativa (polar bears), t.nelsoni (african carnivores and humivorans), and t.britovi (carnivores in europe and west asia). See J Dupouy-Camt, W Kociecka, F Brusci, FBolas-Fernandez, E Pozio Opinion on the diagnosis and treatment of human trichothecosis Expert Opinion on Pharmacology Vol.3(2002). And Id.

Nematode (roundworm) trichuris cause infections in humans that are known to be whipworms. See Cooper, E.S. & Bundy, d.a.p. (1988.) trichoris not manual. 301-306. treatment involves administration of the drug metronidazole. Additionally, albendazole is used as a treatment. And Id.

Typhoid fever is a life-threatening disease caused by salmonella typhi bacteria. See Ryan, Kenneth j.and Stanley falhow, "salmonella," In sherrisical Microbiology: an Introduction to infection Diseases, edge by keneth j.ryan.norwalk, CT: appleton and Lange, 1994 three commonly prescribed antibiotics were ampicillin, trimethoprim/sulfamethoxazole, and ciprofloxacin. And Id.

Vibrio parahaemolyticus is a bacterium of the same family as the cholera-causing bacterium. It lives in slightly salty saline, causing gastrointestinal disease in humans. See World Health Organization farm No.107 Cholera (March 2000). most cases of Vibrio parahaemolyticus infection do not require treatment. There is no evidence that antibiotic treatment reduces the severity or course of the disease. The patient should drink large amounts of fluid to replenish the fluid lost by diarrhea. In severe or ductile diseases, antibiotics such as tetracycline, ampicillin, or ciprofloxacin may be used. Vibrio vulnificus infections are treated with doxycycline or a tertiary cephalosporin (e.g., ceftazidime). And Id.

Bacterial Vaginosis (BV) is caused by a variety of anaerobic bacteria including: genital-urinary tract infections caused by Gardnerella vaginalis, certain species of Campylobacter, certain species of Bacteroides, and Mycoplasma hominis. See Ferris DG, Litakers MS, Woodward L, Mathis D, HendrichJ. treatment of bacterial vacunosis: a, composition of ormomethion, metronidazole variable gel, and clindamycin variable area.J. Fam practice Vol.41(1995). And Id.

Leprosy is an infection of the skin, peripheral nerves and mucous membranes, resulting in damage, hypopigmentation and loss of sensation (anesthesia), especially in areas of lower body temperature. See World health organization show No.101(Jan. 2000.) basic treatment of outpatients (including prevention in close contact) with multidrug therapy consisting of dapsone, rifampicin, and clofazimine for 3-5 years; in endemic areas Mbovis BCG vaccination was effective. And Id.

Streptococcus digestions and susceptibility studies should be performed to determine the pathogenic organisms and their susceptibility to metronidazole. See Ralph, e.d., and Kirby, w.m.m.: bioassay of metronidazole With Either anion or Aerobic incorporation, j.infect.dis.132: 587-591(Nov.) 1975; or guloid, et al: determination of Metandazole and Its Major machinery metabolism in biological Fluids by High Pressure Liquid Chromatography, Br.J.Clin.Pharmacol.6: 430-432, 1978.

The following examples teach the methods of the embodiments described herein and the use of the disclosed ROM production and release inhibiting compounds. These examples are merely illustrative and do not limit the scope of the described embodiments. The treatment methods described below can be optimized using empirical techniques well known to those of ordinary skill in the art. In addition, the full scope of the embodiments can be achieved by the ordinary artisan using the teachings set forth in the following examples.

Example 1

Helicobacter pylori [ Hp (2-20)]Derived cecropin-like peptide activated human monocytes

Triggering programmed death (apoptosis) of natural killer cells and T cells

Infection with helicobacter pylori causes chronic gastritis, which is characterized by massive mucosal infiltration of inflammatory cells such as monocytes/macrophages. With cecropin-like helicobacter pylori peptides, [ Hp (2-20)]Treatment of human monocytes to induce CD3 epsilon⁺Phenotypic T lymphocytes and CD56⁺Apoptosis of phenotypic natural killer cells. The gastric mucosal component histamine reduces (arrested) T cell and NK cell apoptosis. Histamine can be used as an additive to increase the efficacy of helicobacter pylori vaccine test regimens.

Helicobacter pylori causes chronic, often life-long gastritis in humans. The immune response of the host to H.pylori infection is generally characterized by massive infiltration of the gastric subepithelial layer by phagocytic cells, mainly monocytes/macrophages and neutrophils, and lymphocytes including Natural Killer (NK) cells and T cells that mediate protection against infection. See, Agnihotri et al 1988 characteristics of chromatography of hydrolytic subsections and cytogenetic production in gas triopsy samples from Helicobacter pylori. Scand J gastroenterol.33: 704-9; li et al.1999reactions from resonant mucosae producing one layer of helicobacter infection Dig Sci.44: 116-24; takeuchi et al, 2001 scientific signature of natural killer cell activity indexes with structural carbon: a multivariate analysis, Am jgastroentenol.96: 574-8; ishigami et al 2000 scientific value of intraspecific natural killers cells in scientific cancer. cancer.88: 577-83.

Helicobacter pylori [ Hp (2-20) ] derived cecropin-like peptide activated human monocytes induced natural killer cells and programmed death (apoptosis) of T cells. These inhibitory activities are mediated by oxygen radicals, which are induced by Hp (2-20) and are produced by monocyte NADPH oxidase activation. Histamine dihydrochloride protects NK/T cells from monocyte-induced apoptosis by inhibiting oxygen free radicals produced in monocytes. These effects of histamine are mediated by histamine H2 type receptors. We postulate that (pro) histamine, its analogs with H2 receptor agonist activity, or oxygen radical scavengers/inhibitors may contribute to the enhancement of the host immune response to H.

Reagent

The Hp (2-20) peptide used, AKKVFKRLEKLFSKIQNDK, was synthesized and manipulated as described in Bylund et al 2001. Prosubfamily activity of a cephalosporin-like antibacterial peptide from Helicobacter pylori. antibiotic Agents Chemother. in Press histamine dihydrochloride was produced from Maxim Pharmaceutics, (San Diego), ranitidine hydrochloride was produced from Glaxo (M ö lndal, Sweden.) superoxide dismutase (SOD) and catalase were purchased from Boehringer-Mannheim, Germany.

Isolation of leukocytes

Peripheral blood was obtained from healthy donors from Sahlgren's Hospital, G ö teborg Ficoll-Hypaque concentration gradient centrifugation followed by separation of mononuclear cells into lymphocytes and monocytes using the technique of Convection Centrifugal Elutriation (CCE) as described in detail in the literature, resulting in one fraction (flow rate of 20-22 ml/min) with > 90% mononuclear cells and two fractions of lymphocytes, one of which is enriched in CD3 ε^-/56⁺NK cells (45-50%; at 15-16ml/min), one rich in CD3ε⁺/56^-T cells (70-80% at 13-14 ml/min). See Hansson et al 1996. indication of apoptosis in NK cells by monoclonal-derived reactive genes methods. J Immunol.156: 42-7.

Monocyte chemotaxis and NADPH-oxidase Activity

Determination of NADPH-oxidase Activity isoluminol-enhanced chemiluminescence system (CL) system was used to quantify extracellular Reactive Oxygen Species (ROS). See, Dahlgren, c., Karlsson, a.1999.respiratory burst human neutrophiles.j. immunological Methods 232: 3-14.

Apoptosis assay

Apoptosis was monitored by using flow cytometry as described in the literature. See Mellqvist et al 2000.Natural killer cell dysfunction and dappoptosis induced by cyclic mycology leukotypes: role of reactive oxygen species and regulation by histamine.blood.96: 1961-8 monocytes are shown to be gated to T cells or NK cells and gated to lymphocytes with reduced forward scatter and increased right angle scatter apoptosis characteristics. See Hansson et al 1996. two additional methods were used to determine apoptosis in NK and T cells: the DNA fragments were labeled by terminal deoxynucleotidyl transferase mediated brominated dUTP nicked ends and analyzed by Annexin-V stained DNA strand breaks (analysis of DNA strands) according to the methods described in the literature. See Mellqvist et al; hansson et al 1999 Histamine protects T cells and natural killer cells against inflammatory stress.J. Interferon Cytokine Res.19: 1135-44.

Lymphocyte surface and intracellular antigen detection

Monoclonal antibodies (Becton) labeled with appropriate Fluorescein Isothiocyanate (FITC) -and Phycoerythrin (PE) -as described in the literature& Dickinson，Stockholm，Sweden；10ul/10⁶cells) stained 1 million cells. See Hansson et al 1999 by FACStort with Lysys II software System (Becton)&Dickinson) the cells were analyzed using flow cytometry. Lymphocytes are gated on the basis of forward and right angle scatter. The flow rate was adjusted to < 200 cells per second and at least 5000 cells were analyzed per sample.

Hp (2-20) -induced apoptosis of lymphocytes

Early studies revealed that monocytes/macrophages initiate NK cell function inhibition. The discovery that Hp (2-20) strongly triggers the formation of superoxide ions in phagocytes prompted us to study the effect of Hp (2-20) on monocyte/NK cell or T cell interactions. For this, we cultured monocytes at different concentrations with autologous NK cell-rich lymphocytes and observed NK cell viability.

Characteristic morphological changes in lymphocyte apoptosis were observed after overnight incubation of lymphocytes with Hp (2-20) -activated monocytes. In NK cells and CD3 epsilon⁺Hp (2-20) -induced apoptosis was significant in T cells. Apoptosis of Menmenal lymphocytes by DNA fragmentation analysis (TUNEL analysis) and annexin V staining [ not shown]Confirmed and completely prevented for SOD and catalase (fig. 1). See Mellqvist et al, 2000; hansson et al 1999.

FIG. 1 shows that Hp (2-20) triggers apoptosis of NK cells and T cells. After culture, cells within the lymphoblastoid gates were analyzed for apoptotic morphological features (reduced forward scatter and increased right angle scatter) by using flow cytometry. In A, the data are CD56 which was apoptotic after the following treatments⁺(NK; dark grey bar) or CD3 epsilon⁺(T; open bar) frequency:

cells cultured in medium [ control; (1)]

Lymphocyte + 25% monocyte (2)

Lymphocytes + 25% monocytes + Hp (2-20) [50 μ M; (3)]

Lymphocyte + 50% monocyte (4)

Lymphocytes + 50% monocytes + Hp (2-20) (5).

Inset shows apoptosis induced by Hp (2-20) -activated monocytes in lymphocytes, these data are the mean ± s.e.m. of three independent experiments. The results in B show that in the cell mixture treated with SOD + catalase or histamine (50. mu.M), alone or in the presence of the H2 receptor antagonist ranitidine (50. mu.M), lymphocyte apoptosis was induced by 25% monocytes (light grey bars) or 50% monocytes (dark grey bars) activated with Hp (2-20).

Effect of Histamine on NADPH-oxidase Activity

Histamine inhibits Hp (2-20) -induced free radical production and restores lymphocyte function and viability. Previous studies have shown that histamine reduces or inhibits NADPH-oxidase dependent oxygen radical formation by monocytes and other phagocytic cells. See Mellqvist et al.2000. the relatively high concentrations of histamine [ about 10-100. mu.M ] normally present in the gastric mucosa led us to study the effect of histamine on Hp (2-20) -induced oxygen radical formation in monocytes. See Bechi et al.1993.Reflux-related scientific microbiological assay in association with organized microbiological assay content in humanus. gastroenterology.104: 1057-63; lonroth, et al 1990. Histaminevitalism in human gastric mucosa. Effect of gastric stimulation. gastric physiology.98: 921-8 histamine significantly inhibited Hp (2-20) -induced oxygen free radical formation, and the specific histamine H2 receptor antagonist ranitidine counteracted (reversed) this inhibition. (FIG. 2)

FIG. 2 shows the formation of oxygen free radicals induced by Hp (2-20) -and the inhibition by histamine. Superoxide ion production in panned monocytes was studied by isoluminol-amplified CL (a). Cells were treated with histamine (50 μ M) or ranitidine (50 μ M), a receptor antagonist of H2. Data are mean ± s.e.m. of four independent experiments.

Effect of Histamine on NK cell and T cell function

Early studies showed that histamine protects NK cell and T cell functions by inhibiting the production of oxygen radicals as evidenced by inhibition of phagocytic cells. See Mellqvist et al.2000; we therefore investigated whether histamine protects NK and T cells from monocyte-dependent Hp (2-20) -induced apoptosis. Histamine was found to prevent apoptosis of NK cells and T cells. The histamine-induced NK cell and T cell protection was antagonized by the H2 receptor antagonist ranitidine (figure 3).

FIG. 3 shows Hp (2-20) -induced apoptosis: is inhibited by histamine dihydrochloride. Monocytes and/or lymphocytes are prepared as described in the method. After 16 hours of culture, cells within the lymph gate were analyzed for apoptotic morphology by using flow cytometry (reduction in forward scatter and increase in right angle scatter). Data are the frequency of apoptotic lymphocytes. Histamine dihydrochloride, ranitidine and Hp (2-20) at 50 μ M, catalase at 100U/ml, and SOD at 50U/ml.

Hp (2-20) was added to lymphocytes and monocytes in order to mimic the mononuclear cell infiltration of H.pylori-infected stomach tissue, triggering apoptosis of NK cells and T cells. See agnihotril et al 1998; li et al 1999. these inhibitory activities are prevented by NADPH oxidase-derived oxygen radical scavengers and thus all can be explained by oxygen radicals mediated by Hp (2-20) -induced FPRL1/FPRL 2. Histamine was found to reduce or inhibit Hp (2-20) -induced formation of oxygen free radicals and thus protect NK and T cells from apoptotic cell death. This effect of histamine is mediated by the histamine H2 receptor expressed by monocytes and approximates the concentration of histamine detected in human gastric mucosal tissue sufficient to mediate a protective effect. See Bechi et al.1993; lonroth et al 1990.

Example 2

Histamine dihydrochloride to treat tinea infections

The compounds according to embodiments of the present invention are prepared as creams for topical application according to methods known in the art. Histamine dihydrochloride, a ROM production and release inhibiting compound, at a concentration of 0.08% by weight of the formulation, was added to the cream. Subjects with active tinea infection were selected for 10 cases in each of 2 groups. The first group of 10 subjects with fungal infections, the test group was treated with a cream containing histamine dihydrochloride. The second group, the control group, was treated with a cream consisting of the same ingredients and compounds of the test cream, but lacking histamine dihydrochloride.

Treatment of the subject comprises topical application to the lesion 4-5 times per day. When dealing with fungal neoplasms (growth), care was taken not to contaminate the new area with fungal spores. The time to cure was shortened in the test subjects compared to the control.

Example 3

Treatment of microbial infections in combination with other chemotherapeutic agents

The ability of the compositions of the embodiments to promote the recovery of infections caused by microorganisms, including yeast, fungi, bacteria, protozoa, parasites, and amoebae, was next investigated using standard compositions. The ability of the ROM production and release inhibiting compounds of the embodiments to increase the efficacy of an antibacterial agent was evaluated in 2 groups of subjects, 10 cases per group. No subjects had active infection at the beginning of the study. Group I subjects received typical antibacterial agents used to treat specific infections according to the dosages given by the manufacturer. Group II subjects received an equivalent dose of the same antibacterial agent and applied histamine dihydrochloride as a ROM production and release inhibiting compound appropriate for the type and location of microbial infection at 0.08% by weight. The time to recovery was then monitored for each group of patients. Subjects receiving both the antibacterial agent and the ROM inhibiting compound demonstrated an increased recovery time.

Example 4

Treatment of ulcers caused by helicobacter pylori using controlled release devices

Treatment of patients diagnosed with an ulcer caused by helicobacter pylori with the compounds of the embodiments. The controlled release device is supplemented with an effective amount of the ROM inhibiting compound NADPH oxidase inhibitor diphenyleneiodonium, and administered to the patient orally. As the device resides in the patient's stomach, it continues to present the compounds of the embodiments and break down to allow excretion from the body. The compounds of the embodiments are used in combination with typical chemotherapeutic agents for such infections such as amoxicillin, clarithromycin, tetracycline, or metronidazole. Administration of diphenyleneiodonium is effective in accelerating the treatment of gastrointestinal ulcers.

Example 5

Use of spray for treating pulmonary infection of streptococcus pneumoniae

A subject diagnosed with streptococcus pneumoniae is treated with the compounds of the embodiments in spray form. The spray is secured against the oro-nasal cavity of a patient with a respiratory infection. Sprays are used to present an aerosol mist when a patient inhales deeply. Sprays can contain either an effective amount of a formulation as described herein, alone or in admixture with a chemotherapeutic agent commonly used for administration of such infections, such as cephalexin. The ROM inhibiting compound NADPH oxidase inhibitor diphenyleneiodonium at a concentration of 0.05% by weight of the formulation was presented as a mist by spraying into the patient's lungs. Administration of diphenyleneiodonium promoted recovery in patients with pneumonia.

Example 6

Treatment of ocular infections with chlamydia trachomatis using eye drops and/or eye ointments

Subjects with ocular infections with Chlamydia trachomatis were treated with 0.09% by weight of the formulation of histamine dihydrochloride in the compositions of the embodiments. Commercially available eye drops are well known in the art. In addition, eye drops, preferably in the form of drops, contain synomycin. The eye drops were applied to the eyes 1 time every 3 hours. Solutions containing only the ROM production and release inhibiting compounds were administered hourly to alleviate discomfort in the subject. The application of the eye drop reduces the time of bacterial infection, the damage caused by bacterial infection, and the discomfort of the patient.

Example 7

Treatment of gastrointestinal infections with trichuris (ASCARIS trichourisis) using suppositories and/or enemas

Children exhibiting symptoms of parasitic infection are treated with the compounds of the embodiments. Suppositories containing the formulations described herein are placed into the rectum of patients with Ascaris trichoderma ("trichuris"). Gradual release of the formulation on the suppository will reduce inflammation. In addition, suppositories containing the formulations described herein are administered rectally, and in addition antiparasitic agents such as piperazine citrate, mebendazole, albendazole or pyrantel pamoate are suitably administered to patients infected with Ascaris trichoderma to kill the parasites and reduce inflammation. Similarly, for parasites located at higher levels in the human gastrointestinal tract, such as roundworm (roundworm) infections, enemas are used to present the above compounds in addition to anti-parasitic agents for the same purpose of eliminating parasites and reducing inflammation. Suppository replacement and repeated enema administration in addition to other chemotherapeutic agents to shorten the healing time and expel parasites.

Example 8

Treatment of hemozoin infections using intravenous or intraarterial injections

Confirmed patients with malaria caused by any of the 4 plasmodia were treated by presenting the composition of the embodiments by injection using an intravenous infusion bag or an intra-arterial syringe. Intravenous or intraarterial injections contain either an effective amount of the composition disclosed herein alone or in admixture with an effective amount of a suitable chemotherapeutic agent, such as chloroquine phosphate, sulfa drugs and primethamine. The composition is dispersed into the blood stream and liver where protozoa reside by injection to eliminate plasmodium from the patient and reduce inflammation. Intravenous or intra-arterial administration was 1 time per hour to reduce discomfort in the subject. The use of this solution will accelerate the shedding of the patient from plasmodium.

Example 9

Treatment of diarrhea by oral administration of capsules

In addition to the administration of an appropriate chemotherapeutic agent such as aminoglycoside, chloramphenicol, trimethoprim sulfamethoxazole, doxycycline or fluoroquinolone, subjects suffering from diarrhea were treated with a capsule containing the ROM inhibiting compound NADPH oxidase inhibitor diphenyleneiodonium at a formulation weight concentration of 0.8%. The diarrhea is due to any number of pathogenic genera, species, or strains of escherichia coli, proteus mirabilis, salmonella enteritidis, klebsiella, yersinia, shigella, serratia, candida, giardia, cryptosporidium, vibrio cholerae, campylobacter, ascaris, and the like, that cause diarrhea or similar forms of gastrointestinal disease. The treatment consists of taking 3-10 capsules per day for 7-30 days (depending on the cause of the infection). Administration of diphenyleneiodonium is effective in accelerating diarrhea treatment in a subject.

Example 10

Treatment of sepsis using intravenous or intra-arterial injection

Patients with established sepsis are treated by administering the composition of the described embodiments by injection using an intravenous infusion bag or an intra-arterial syringe. Intravenous or intra-arterial injections contain either an effective amount of the compositions disclosed herein alone or in combination with an effective amount of an appropriate chemotherapeutic agent specific for the organism responsible for the sepsis. The composition is dispersed into the bloodstream where the septic organism inhabits by injection to destroy plasmodium from the patient and reduce inflammation. Intravenous or intra-arterial administration was 1 time per hour to reduce discomfort in the subject. The use of this solution will accelerate the patient's escape from the cause of sepsis.

Example 11

Treatment of dental infections using toothpaste and mouthwash

Patients suffering from dental infections caused by Streptococcus mutans were treated with toothpastes and mouthwashes containing 0.05% by weight of the formulation of the ROM inhibiting compound NADPH oxidase inhibitor diphenyleneiodonium. Treatment consisted of brushing the teeth 5 times a day with this toothbrush and applying a rinse for 7 days. Administration of diphenyleneiodonium is effective in treating dental infections in a subject.

Claims (45)

1. A method of inhibiting or reducing enzymatically produced ROM-mediated oxidative damage to the skin or mucosa of a patient, said method comprising the step of topically administering an effective amount of a ROM production and release inhibiting compound in a pharmaceutically acceptable carrier to a subject suffering from ROM-mediated oxidative damage at the site of infection in said patient.

2. The method of claim 1, wherein the ROM-mediated oxidative damage to the site of infection in the patient is a bacterial disease selected from the group consisting of: streptococci, staphylococci, enterococci family members, helicobacter, Neisseria, Chlamydia, mycobacteria, Treponema, Pseudomonas, Haemophilus, Mycoplasma, Clostridium, Actinobacillus, Rickettsia, Legionella, Listeria, Leptospira, and the like.

3. The method of claim 1, wherein the ROM-mediated oxidative damage to the skin or mucosa of the patient is a fungal disease selected from the group consisting of: tinea, candida, histoplasma, sporothrix, blastomyces, cryptococcus, aspergillus, malassezia, and the like.

4. The method of claim 1, wherein the ROM-mediated oxidative damage to the skin or mucosa of the patient is a parasitic disease selected from the group consisting of: roundworms, schizocephala (diphyllobothrium), jawboloids, wuchereria, bruneid, onchocerciasis, ophiocladia, mansenworm, and the like.

5. The method of claim 1, wherein the ROM-mediated oxidative damage to the skin or mucosa of the patient is a protozoan disease selected from the group consisting of: plasmodium, giardia, trichomonas, toxoplasma, leishmania, and the like.

6.The method of claim 1, wherein said ROM production and release inhibiting compound is selected from the group consisting of histamine, histamine dihydrochloride, histamine diphosphate, other histamine salts, esters, prodrugs, H₂Receptor agonists, 5-hydroxytryptamine and 5-HT agonists.

7.The method of claim 1, wherein said ROM production and release inhibiting compound promotes the release of endogenous histamine stores.

8. The method of claim 7, wherein said compound that promotes endogenous histamine storage release is selected from the group consisting of IL-3, retinoic acid, 9-cis-retinoic acid, all-trans retinoic acid, and allergens.

9.A composition comprising an effective amount of a compound that inhibits the production or release of enzymatically active ROMs, said compound being suitable for intravenous, intraarterial, topical, oral, anal, genital, transdermal, inhalation, intranodal, and intramuscular administration in a pharmaceutically acceptable carrier.

10. The composition of claim 9, wherein said compound is selected from the group consisting of histamine, histamine dihydrochloride, histamine diphosphate, other histamine salts, esters, prodrugs, H₂Receptor agonists, 5-hydroxytryptamine and 5-HT agonists.

11. The composition of claim 9, wherein the compound is a compound that promotes the release of endogenous histamine stores.

12. The composition of claim 11, wherein said compound that promotes the release of endogenous histamine stores is selected from the group consisting of IL-3, retinoic acid, 9-cis-retinoic acid, all-trans retinoic acid, and allergens.

13. The composition of claim 9, wherein the pharmaceutically acceptable carrier is a cosmetic.

14. The composition of claim 13, wherein the pharmaceutically acceptable carrier is a soap.

15. The composition of claim 13, wherein the pharmaceutically acceptable carrier is a wound dressing.

16. The composition of claim 13, wherein the pharmaceutically acceptable carrier is a nebulizer.

17. The composition of claim 13, wherein said pharmaceutically acceptable carrier is a transdermal patch.

18. The composition of claim 13, wherein the pharmaceutically acceptable carrier is a toothpaste.

19. The composition of claim 13, wherein the pharmaceutically acceptable carrier is a mouthwash.

20. The composition of claim 13, wherein the pharmaceutically acceptable carrier is a lotion.

21. The composition of claim 9, wherein the pharmaceutically acceptable carrier is a suppository.

22. The composition of claim 9, wherein the pharmaceutically acceptable carrier is a liquid capable of intravenous or intra-arterial administration.

23. The composition of claim 9, wherein the pharmaceutically acceptable carrier is an inhalant capable of inhalation.

24. The composition of claim 9, wherein the inhalation is administered by a nebulizer or inhaler.

25. The composition of claim 9, wherein the pharmaceutically acceptable carrier is administered orally.

26. The composition of claim 9, wherein said oral administration is via a pill, capsule or lozenge.

27. The composition of claim 9, wherein the pharmaceutically acceptable carrier is an eye drop or eye ointment.

28. The composition of claim 9, wherein the pharmaceutically acceptable carrier is a controlled release device.

29. The composition of claim 9, wherein the controlled release device is biodegradable in a subject.

30. The composition of claim 9, wherein the controlled release means is not biodegradable but excreted by the subject's excreta.

31. The composition of claim 9, wherein the pharmaceutically acceptable carrier is a surgical plant.

32. The composition of claim 9, wherein the surgical plant is embedded within a tissue of a subject.

33. The composition of claim 9, wherein the surgical plant is attached to the site of infection in or on the subject.

34. A method of preparing a composition for topical administration of a compound that inhibits the production and release of enzymatically produced ROMs, comprising:

providing a pharmaceutically acceptable carrier and an effective concentration of histamine to treat ROM-mediated damage to skin caused by a microbial infection; and

forming a composition comprising a pharmaceutically acceptable carrier and said compound that inhibits the production and release of enzymatically produced ROMs.

35. The method of claim 34, wherein said compound is selected from the group consisting of histamine, histamine dihydrochloride, histamine phosphate, other histamine salts, esters, prodrugs, H₂Receptor agonists, 5-hydroxytryptamine and 5-HT agonists.

36. The composition of claim 34, wherein said compound is a compound that promotes the release of endogenous histamine stores.

37. The method of claim 34, wherein the pharmaceutically acceptable carrier is a lozenge, mouthwash, toothpaste, cosmetic, transdermal patch, intravenous injection, intra-arterial injection, suppository, enema, eye drop, eye ointment, lotion, surgical implant, controlled release device, soap, pill, capsule, inhalant, nebulizer, or wound dressing.

38. The method of claim 34, wherein the method of treatment is of a parasite, yeast, fungus, protozoan or other parasitic infectious disease that causes inflammation.

39. A method of treating a microbial infection, said method consisting of the steps of:

diagnosing patient-associated microbial infection

Administering to the patient an effective amount of an appropriate chemotherapeutic agent; and

administering to the subject an effective amount of a compound selected from histamine, other H, to inhibit the production and release of intracellular hydrogen peroxide₂A compound of the group consisting of a receptor agonist and 5-hydroxytryptamine.

40. The method of claim 39, wherein said appropriate chemotherapeutic agent and said compound effective to inhibit the production and release of intracellular hydrogen peroxide are administered preferably simultaneously.

41. The method of claim 39, wherein administration of said appropriate chemotherapeutic agent is preferably within 1 hour of administration of said compound effective to inhibit the production and release of hydrogen peroxide in the cell.

42. The method of claim 39, wherein said compound effective to inhibit the production and release of hydrogen peroxide in a cell is administered in a dose of from about 0.1 to about 10 mg/day.

43. The method of claim 39, wherein the compound effective to inhibit the production and release of hydrogen peroxide within the cell is administered alone.

44. The method of claim 39, wherein said compound effective to inhibit the production and release of hydrogen peroxide in a cell is administered in combination with an effective amount of an appropriate chemotherapeutic agent.

45. A method of treating a microbial infection, the method comprising:

administered to a patient receiving chemotherapy effective to inhibit the production and release of intracellular hydrogen peroxide selected from

Histamine, other H₂An effective amount of a compound of the group consisting of a receptor agonist and 5-hydroxytryptamine.